10.4081/btvb.2024.104
Although the use of prophylaxis regimens with prolonged half-life factors is now widespread in the world of hemophilia A, there is a lack of real-life evidence on the impact of these products on joint health, adherence, and quality of life of patients. Turoctocog alfa pegol is a glycoPEGylated recombinant factor VIII (FVIII) with an extended half-life (EHL), developed for prophylaxis, treatment of bleeds, and perioperative management in patients with hemophilia A. We report here on three cases of three patients affected by severe hemophilia A, with variable bleeding phenotype and lifestyle, to describe our clinical practice on prophylaxis with turoctocog alfa pegol. As confirmed in our cases, FVIII trough levels remained coherent with those experienced in the registration trial after the switch to the commercial EHL drug. Moreover, the cases highlight how the current clinical management of hemophilia can personalize treatment in several specific conditions.
application/pdf
2785-5309
104
1
en
Alberto Tosetto
https://creativecommons.org/licenses/by-nc/4.0
Bleeding, Thrombosis and Vascular Biology
extended half-life
Tailored therapy with turoctocog alfa pegol according to patient’s lifestyle and hemorrhagic phenotype: from clinical trial to real-life
Text.Serial.Journal
https://www.btvb.org/btvb
3
Case Reports
2024-04-22
2023-12-14
2024-03-01
2024-04-22
Bleed Thromb Vascul Biol
Alberto Tosetto
2024/04/22
10.4081/btvb.2024.104
Hemophilia and Thrombosis Center, Department of Hematology, Local Socio-Health Unit 8 (AULSS8) Berica, Vicenza
2785-5309
1
extended half-life
en
Tailored therapy with turoctocog alfa pegol according to patient’s lifestyle and hemorrhagic phenotype: from clinical trial to real-life
https://www.btvb.org/btvb/article/download/104/102
3
                                                                                                                       CASE REPORT

Tailored therapy with turoctocog alfa pegol according to patient’s
lifestyle and hemorrhagic phenotype: from clinical trial to real-life
Ilaria Nichele, Giuseppe Carli, Alberto Tosetto

Hemophilia and Thrombosis Center, Department of Hematology, Local Socio-Health Unit 8 (AULSS8) Berica, Vicenza, Italy



ABSTRACT
     Although the use of prophylaxis regimens with prolonged half-life factors is now widespread in the world of hemophilia A, there
is a lack of real-life evidence on the impact of these products on joint health, adherence, and quality of life of patients. Turoctocog alfa
pegol is a glycoPEGylated recombinant factor VIII (FVIII) with an extended half-life (EHL), developed for prophylaxis, treatment of
bleeds, and perioperative management in patients with hemophilia A. We report here on three cases of three patients affected by severe
                                                                          hemophilia A, with variable bleeding phenotype and lifestyle,
                                                                          to describe our clinical practice on prophylaxis with turoctocog
                                                                          alfa pegol. As confirmed in our cases, FVIII trough levels re-
   Correspondence: Alberto Tosetto, Hemophilia and Thrombosis             mained coherent with those experienced in the registration trial




                                                                                               ly
   Center, Hematology Department, Local Socio-Health Unit 8               after the switch to the commercial EHL drug. Moreover, the
   (AULSS8) Berica, Vicenza, Italy.




                                                                                       on
                                                                          cases highlight how the current clinical management of hemo-
   E-mail: alberto.tosetto@aulss8.veneto.it
                                                                          philia can personalize treatment in several specific conditions.
  Key words: hemophilia A, tailorized therapy, turoctocog alfa pegol,




                                                                                  e
  recombinant factor VIII, extended half-life.

  Contributions: the authors contributed equally.

  Conflict of interest: the authors declare no potential conflict of in-
                                                                            us
                                                                             Introduction
                                                                                  Thanks to the evolution of hemophilia treatments, recombi-
                                                                            al
  terest.                                                                    nant factor VIII (rFVIII) with an extended half-life (EHL) is
                                                                             available nowadays. Thanks to modified pharmacokinetics (PK)
                                                         ci

  Funding: the authors received no specific funding for this work.           and innovative tested therapeutic dosages and schemes, they
  The editorial assistance was provided by CORESEARCH SRL
                                                       er


                                                                             allow the association of a reduced number of intravenous infu-
  through a Novo Nordisk S.p.A. unconditional grant. The authors
                                                                             sions with greater patient protection from bleeding events.
  of the publication are fully responsible for the content and conclu-
                                                      m



  sions. Novo Nordisk S.p.A. did not influence and has not been in-               Despite the widespread use of prophylaxis regimens with
  volved in the data interpretation presented in the manuscript.             EHL life factors, there is a lack of real-life evidence on the im-
                                          om




                                                                             pact of these products on joint health, adherence, and quality of
  Ethical approval and consent to participate: ethical approval and          life of patients.
  informed consent were obtained.                                                 Turoctocog alfa pegol (N8-GP; Novo Nordisk A/S,
                                    -c




                                                                             Bagsvaerd, Denmark) is a glycoPEGylated rFVIII with an EHL.
  Availability of data and materials: data and materials are available
                                                                             This drug requires less frequent dosing and has a half-life of up
  by the authors.
                           on




                                                                             to 1.6-fold longer than standard FVIII products.1-3
  Acknowledgments: the authors thank Alessandra Di Lelio and An-                  Turoctocog alfa pegol was approved by the United States
                     N




  tonio Nicolucci (CORESEARCH - Center for Outcomes Research                 Food and Drug Administration (adults/adolescents and children)
  and Clinical Epidemiology, Pescara, Italy) for their support in med-       and the European Medicines Agency (adults/adolescents) for
  ical writing and editorial assistance.                                     prophylaxis, treatment of bleeds, and perioperative management
                                                                             in patients with hemophilia.4,5 Safety and efficacy in the prophy-
  Received: 14 December 2023.
                                                                             laxis and treatment of bleeds in adults/adolescents and children
  Accepted: 15 March 2024.
                                                                             with severe hemophilia A have been demonstrated in the pivotal
  Publisher’s note: all claims expressed in this article are solely those    phase III Pathfinder 2 and 5 trials.1,6
  of the authors and do not necessarily represent those of their affili-          We report here three cases of three patients affected by se-
  ated organizations, or those of the publisher, the editors and the re-     vere hemophilia A, with variable bleeding phenotype and
  viewers. Any product that may be evaluated in this article or claim        lifestyle, to describe our clinical practice on prophylaxis with
  that may be made by its manufacturer is not guaranteed or endorsed         turoctocog alfa pegol, in the Department of Hematology of Vi-
  by the publisher.                                                          cenza Hospital.
  ©
   Copyright: the Author(s), 2024
  Licensee PAGEPress, Italy
  Bleeding, Thrombosis and Vascular Biology 2024; 3:104                      Case reports
  doi:10.4081/btvb.2024.104
                                                                             First therapeutic scheme: every four days
  This work is licensed under a Creative Commons Attribution-
  NonCommercial 4.0 International License (CC BY-NC 4.0).                         The first subject is a patient with severe hemophilia A (base-
                                                                             line FVIII levels <1%), no history of inhibitor, severely disabling


                                             Bleeding, Thrombosis and Vascular Biology 2024; 3:104
18                                                            I. Nichele et al.




hemophilic arthropathy, needing multi-district prosthetic sur-               Table 2 shows the estimated FVIII plasma concentration
gery, with concomitant hepatitis C virus (HCV) infection, which           (U/mL).
has been eradicated.
    The patient was treated with “on-demand” plasma FVIII                 Third therapeutic scheme: biweekly
concentrates from August 1993 until July 2012 (number of
plasma FVIII exposures >150).                                                  The third subject is a patient with severe hemophilia A, with-
    In July 2012, when he was 58 years old, he was enrolled in            out a history of inhibitor, in prophylaxis since the age of 3 years
the Pathfinder 2 study (NN7088-3859), initially with the “on-             with rFVIII twice a week. The patient had concomitant hemo-
demand” regimen at a dose of 50 U/kg, then from January 2013              philic arthropathy affecting the ankle and left knee.
with a prophylaxis regimen at a dose of 50 U/kg every four days                He was enrolled in the Pathfinder 5 study (NN7088-3885) in
and from June 2015 at a dose of 75 U/kg every seven days, ac-             February 2013 with a biweekly scheme. FVIII levels after 96
cording to the study protocol. FVIII trough levels were 1% with           hours were 4% with the one-stage method and 6% with the chro-
the one-stage method and 2% with the chromogenic method                   mogenic method.
(weekly regimen).                                                              During the study, the patient reported some hemorrhagic
    In September 2020, the patient switched to the commercial             episodes, mainly of post-traumatic nature.
drug, at a dose of 3000 U every four days (about 45 U/kg), with                In July 2020, the patient was switched to the commercial drug,
FVIII trough levels of 4% with the one-stage method and 5%                at the same therapeutic scheme and with substantially overlapping
                                                                          PK data (FVIII of 6% with the one-stage method, 5% with the




                                                                                                     ly
with the chromogenic method. The patient reported good com-
pliance and good control of chronic joint pain.                           chromogenic method after 96 hours). No bleeding events were re-




                                                                                             on
    In March 2021, the patient’s good compliance, the absence             ported.
of bleeding complications reported over the months and the pa-                 FVIII PK analysis was assessed using WAPPS-Hemo.8 A time
tient’s almost sedentary lifestyle led to the decision to switch to       point at 32 minutes post-infusion was used for the WAPPS-Hemo




                                                                                        e
a weekly treatment regimen.                                               assessments.
                                                                               The FVIII activity measurements for the PK assessments were
    FVIII activity results were assessed using the Web-Acces-
sible     Population
(WAPPS-Hemo).8
                        Pharmacokinetics-Service-Hemophilia
                                                                          method).
                                                                                  us
                                                                          performed using a two-stage coagulation test (chromogenic
                                                                         al
    Two time points at 15 minutes and 72 hours post-infusion
were used for the WAPPS-Hemo assessments.
                                                           ci

    The FVIII activity measurements for the PK assessments                Table 1. Estimated factor VIII plasma concentration (U/mL),
were performed using a chromogenic assay.
                                                         er


                                                                          assessed by the Web-Accessible Population Pharmacokinetics-
    Table 1 shows the estimated FVIII plasma concentration                Service-Hemophilia. First therapeutic scheme.
(U/mL).
                                                        m



                                                                           Time, days      Conservative       Balanced        Optimistic
                                              om




Second therapeutic scheme: weekly                                          1                    0.446            0.514            0.592
                                                                           2                    0.224            0.264            0.312
    The second subject is a patient with severe hemophilia A
                                                                           3                    0.111            0.137            0.170
(baseline FVIII levels <1%), without a history of inhibitor, with
                                        -c




eradicated HCV infection and ankle and right knee arthropathy.             4                    0.055            0.072            0.095
                                                                           5                    0.029            0.039            0.055
                                on




    This patient was initially on on-demand therapy with rFVIII;
from 2009 he was on prophylaxis with rFVIII at the dose of                 6                    0.016            0.022            0.032
2000 U, twice a week.                                                      7                    0.010            0.014            0.020
                           N




    He was enrolled in the Pathfinder 2 study (NN7088-3859)                8                    0.007            0.010            0.013
in August 2012, initially at the regimen of 50 U/kg every four
days, then at about 70 U/kg every seven days, with the mainte-
nance of FVIII through levels at 1% with the one-stage method
and 2% with the chromogenic method.                                       Table 2. Estimated factor VIII plasma concentration (U/mL),
    No bleeding events occurred during the experimental study.            assessed by the Web-Accessible Population Pharmacokinetics-
                                                                          Service-Hemophilia. Second therapeutic scheme.
Chronic joint pain in the ankle and right knee significantly im-
proved.                                                                    Time, days      Conservative       Balanced        Optimistic
    Since July 2020, the patient has been in treatment with the            1                    0.837           0.3961            1.102
commercial drug at the same therapeutic regimen (75 U/kg) with
                                                                           2                    0.392            0.465            0.551
FVIII trough levels consistent with the product PK (FVIII trough
levels of 2% with one stage method; 1% with the chromogenic                3                    0.180            0.226            0.284
method). No bleeding events were reported. The drug led to                 4                    0.083            0.111            0.150
good control of chronic joint pain.                                        5                    0.040            0.056            0.080
    FVIII PK analysis was assessed using WAPPS-Hemo.8 A                    6                    0.020            0.030            0.044
time point at 32 minutes post-infusion was used for the WAPPS-
                                                                           7                    0.012            0.017            0.025
Hemo assessments. The FVIII activity measurements for the PK
                                                                           8                    0.008            0.011            0.016
assessments were performed using a two-stage coagulation test
(chromogenic method).                                                      9                    0.006            0.008            0.011


                                        Bleeding, Thrombosis and Vascular Biology 2024; 3:104
                Tailored therapy with turoctocog alfa pegol according to patient’s lifestyle and hemorrhagic phenotype                19



    Table 3 shows the estimated FVIII plasma concentration             phylaxis, with a very active, sporting lifestyle (horseback rid-
(U/mL).                                                                ing, athletics) and with a tendency to bleed, including post-
    Considering the patient’s lifestyle with the need to maintain      traumatic ones.
higher trough levels, a bi-weekly regimen can be continued.                 Good adherence to treatment and good quality of life were
                                                                       reported, together with excellent coverage of the current thera-
                                                                       peutic regimen, both within the experimental protocol and with
Discussion                                                             the commercial drug. Considering the patient’s lifestyle with the
                                                                       need to maintain higher trough levels, a bi-weekly regimen will
    The use of turoctocog alfa pegol in prophylaxis was associ-        be continued.
ated with a particularly low number of bleeds in the Pathfinder             Before the switch to N8-GP, the bleeding tendency of the
study program, allowing to maintain in all patients a trough level     first and second patients was only modest, also in line with the
of at least 3% with a therapy regimen of 50 U/kg every four days       sedentary lifestyle of both. However, especially in the first pa-
and allowing in some selected patients to reach a regimen of ad-       tient, due to advanced arthropathy with exacerbations of joint
ministration once a week with 75 U/Kg.7                                pain, “on-demand” infusions were frequent. The third patient,
    In the described patients, FVIII trough levels remained con-       however, presented a high bleeding tendency, especially post-
sensual to their experience in the registration trial: since this is   traumatic, in line with the very active lifestyle and sometimes
the center with the largest number of cases enrolled, observing        high-impact sport. The switch to N8-GP allowed a clinical im-
the maintenance of results in real life is fundamental.




                                                                                         ly
                                                                       provement in all three patients, reducing the number of addi-
    Moreover, the current cases highlight how the current clin-        tional infusions and the overall consumption of concentrates,




                                                                                 on
ical management of hemophilia can personalize treatment in             resulting in an improvement in costs.
several specific conditions: the treatment has been tailored ac-
cording to the patient’s lifestyle and hemorrhagic phenotype.




                                                                           e
    The first subject is a 66-year-old patient in tertiary prophy-     Conclusions
laxis with severe multi-district arthropathy already with multiple
joint prostheses, low bleeding tendency, sedentary lifestyle and
control of chronic joint pain from the beginning of prophylaxis
                                                                       us   As confirmed in our cases, after the switch to commercial
                                                                       drugs, FVIII levels remained consensual to the ones experienced
                                                                  al
with N8-GP. This drug led to a good management of orthopedic           in the registration trial.
surgery. The same characteristics have been maintained with the             The cases highlight how the current clinical management of
                                                   ci

commercial drug; therefore, after starting the dosage at about 50      hemophilia may allow to personalize the treatment according to
U/kg, the patient was switched to weekly administration.               specific conditions, such as lifestyle and hemorrhagic pheno-
                                                 er


    The second subject is a 48-year-old patient with severe he-        type, in order to improve adherence to treatment and its effec-
mophilia in secondary prophylaxis, with a low bleeding ten-            tiveness. Good adherence to treatment and good quality of life
                                                m




dency and a sedentary lifestyle. The same characteristics of           were reported, together with excellent protection from bleeding.
                                      om




good adherence to treatment and good quality of life with                   These cases can be added to the limited body of evidence
weekly infusions were maintained even with commercial prod-            currently available on turoctocog alfa pegol in real life. Further
ucts, together with the same PK profile compared to the ex-            investigation is required to study the impact of this product in
                                -c




perimental product (slight discrepancies depending on the              real life.
laboratory method – one stage versus chromogenic – however,
                        on




possible in the case of low values). Considering the patient’s
characteristics, lifestyle and PK, he will go on with the estab-       References
lished regimen.
                   N




    The third subject is a 20-year-old patient in secondary pro-        1. Giangrande P, Andreeva T, Chowdary P, et al. Clinical evalu-
                                                                           ation of glycoPEGylated recombinant FVIII: efficacy and
                                                                           safety in severe haemophilia A. Thromb Haemost 2017;117:
                                                                           252-61.
Table 3. Estimated factor VIII plasma concentration (U/mL),             2. Tiede A, Brand B, Fischer R, et al. Enhancing the pharmaco-
assessed by the Web-Accessible Population Pharmacokinetics-                kinetic properties of recombinant factor VIII: first-in-human
Service-Hemophilia. Third therapeutic scheme.
                                                                           trial of glycoPEGylated recombinant factor VIII in patients
Time, days        Conservative       Balanced        Optimistic            with hemophilia A. J Thromb Haemost 2013;11:670-8.
                                                                        3. Tosetto A, Neff A, Lentz SR, et al. Turoctocog alfa pegol pro-
1                     0.693            0.794            0.911
                                                                           vides effective management for major and minor surgical pro-
2                     0.349            0.413            0.489
                                                                           cedures in patients across all age groups with severe
3                     0.173            0.216            0.271              haemophilia A: Full data set from the pathfinder 3 and 5 phase
4                     0.086            0.114            0.153              III trials. Haemophilia 2020;26:450-8.
5                     0.044            0.061            0.088           4. U.S. Food and Drug Administration. Esperoct prescribing in-
6                     0.023            0.034            0.051              formation. Available from: https://www.fda.gov/media/
                                                                           120351/download (accessed on October 13th, 2021).
7                     0.014            0.020            0.031
                                                                        5. European Medicines Agency. Esperoct. Available from:
8                     0.009            0.013            0.020
                                                                           https://www.ema.europa.eu/en/medicines/human/EPAR/es-
9                     0.007            0.009            0.013              peroct (accessed on October 13th, 2021).


                                         Bleeding, Thrombosis and Vascular Biology 2024; 3:104
20                                                          I. Nichele et al.




6. Meunier S, Alamelu J, Ehrenforth S, et al. Safety and efficacy            adolescents with hemophilia A: final results from pathfinder2.
   of a glycoPEGylated rFVIII (turoctocog alpha pegol, N8-GP)                J Thromb Haemost 2020;18:5-14.
   in paediatric patients with severe haemophilia A. Thromb               8. Iorio A, Keepanasseril A, Foster G, et al. Development of a
   Haemost 2017;117:1705-13.                                                 web-accessible population pharmacokinetic service-hemo-
7. Giangrande P, Abdul Karim F, Nemes L, et al. Long-term                    philia (WAPPS-Hemo): study protocol. JMIR Res Protoc
   safety and efficacy of N8-GP in previously treated adults and             2016;e239.




                                                                                                   ly
                                                                                           on
                                                                                      e
                                                                                us
                                                                       al
                                                         ci
                                                       er
                                                      m
                                            om
                                      -c
                               on
                          N




                                       Bleeding, Thrombosis and Vascular Biology 2024; 3:104
