Refixia® now also offers children with hemophilia B new treatment perspectives right from the start

14.08.2023 12:57

Novo Nordisk announced on August 14 that Refixia® (Nonacoq beta pegol) has received an extension of approval from the European Medicines Agency (EMA) for the prevention and treatment of bleeding in children with hemophilia B aged 0 years and older.

Refixia®, a glycopegylated recombinant factor IX (rFIX) with an extended half-life, can therefore now also be used in children with this rare congenital blood clotting disorder without age restrictions.1 Studies confirmed the effectiveness and safety of Refixia® in both pretreated and pretreated children in previously untreated children with hemophilia B between 0 and 12 years. [2-4]

For people with hemophilia, replacing the missing clotting factors with plasma-derived or recombinant factors is recommended. In hemophilia B, factor IX is missing. According to the World Federation of Hemophilia (WFH), for optimal treatment of children with severe hemophilia B (FIX activity < 1 %), prophylaxis with FIX should be started under the age of 3 years before the first joint bleeding. [5] However, frequent injections are often difficult in younger children. rFIX products with extended half-life (EHL) are a good option because they are injected less frequently and result in consistently higher FIX activity than standard rFIX products. [6,7] Refixia® is a once-weekly administered rFIX with an extended half-life for the prophylaxis and treatment of bleeding in hemophilia B, which is now also approved for children aged 0 and over. [1]

Effective hemostasis with Refixia® in children with hemophilia B

The pediatric approval of Refixia® is based on the results of two multi-national, single-arm, uncontrolled, open-label phase III studies, paradigm 5 and paradigm 6, which evaluated the efficacy and safety of Refixia® in children with moderate to severe hemophilia B (FIX activity ≤ 2 %): paradigm 5 - consisting of the 52-week main phase [2] and the subsequent extension phase [3] - examined children ≤ 12 years old who were pretreated with other FIX products [2, 3] and paradigm 6 untreated or only minimally pretreated children ≤ 6 years of age [4].

In both studies, the children received the recommended dosage of 40 IU/kg body weight of Refixia® once a week for bleeding prophylaxis [2-4]; In paradigm 6, individualized dosage for preprophylaxis was also possible [4].

Effective bleeding prophylaxis with Refixia® in previously treated children

Of the 25 patients enrolled in paradigm 5 at baseline, 24 completed the 52-week phase: 11 children aged 0–6 years and 13 children aged 7–12 years. [2] At the time of the 5-year follow-up analysis, 17 patients were still in the extension study. [3] The 5-year analysis included 116.44 patient-years and 6,194 exposure days (ED). The median number of Refixia® injections for prophylaxis was 279. None of the children developed inhibitors against FIX or anti-PEG antibodies. [3]

It was shown that Refixia® could offer effective prophylaxis: 20 % children remained completely free of bleeding, 40 % had no joint bleeding and 64 % had no spontaneous bleeding.3 The median annualized total bleeding rate (ABR) was in the 5- Annual analysis at 0.68. [3] High mean FIX trough levels were achieved during prophylaxis with Refixia®: 19.2 % in children aged 7 to ≤ 12 years and 16.6 % in children ≤ 6 years.3 Refixia® also proved to be reliable in the Bleeding control: In 88.7 % of bleeding, Refixia® led to successful – i.e. “excellent” or “good” – hemostasis. The majority (93 %) of bleeding events could be treated with one or two injections of Refixia®. [3]

Effectiveness of Refixia® even in children who have not been previously treated

The paradigm 5 study includes 4 phases: The screening visit (phase 1) was followed by the (main) phase 2 (duration: 1 - 3 years), in which the children initially received either once-weekly prophylaxis with Refixia® until 50 ED were reached, or preprophylaxis with individualized dosage of Refixia® (until age ≤ 24 months or 20 ED). Weekly prophylaxis was then carried out until 50 ED was reached. In phase 3, the children received an additional 50 ED as prophylaxis (up to 100 ED). In the subsequent phase 4, they received Refixia® prophylaxis until the end of the study. [4]

At the time of the interim analysis (data cutoff August 31, 2018) of the study, 37 of the 38 included children with severe hemophilia (FIX activity ≤ 2 %) had received Refixia®. They were untreated before the start of the study or had received a maximum of 3 EDs with a FIX product. Their median age was 1.0 years [0 – 4]. A total of 2,833 EDs – around 65 patient years – were included in the analysis. [4]

31 children with ≥ 10 ED and 2 children who developed FIX inhibitors were classified as “at risk patients”. Two of them developed high titer FIX inhibitors during the course of the study. The estimated incidence for FIX inhibitors of 6.1 % was in the expected range for previously untreated patients. The two children were removed from the study. No other safety signals, including thromboembolic events, were identified. [4]

Refixia® proved to be effective in the study: 67.9 % (19/28) of the children in the prophylaxis group remained bleeding-free, 85.7 % (24/28) of the children had no spontaneous bleeding. The median overall ABR in the prophylaxis group was 0.0*. [4] In paradigm 6, Refixia® was also shown to be reliable in controlling bleeding: Treatment with Refixia® was rated “excellent” or “good” in 93.8 % of bleeding in the total population and in 93.3 % in the prophylaxis group. rated. In the prophylaxis group, a single injection of Refixia® was sufficient for hemostasis in 100 % of bleeding events; in the preprophylaxis group, this was the case in 81.8 %. [4] The estimated mean FIX activity over the entire study period was 15.0 % in the prophylaxis group. The FIX trough level in the prophylaxis group was 0.6 % after 1 ED and increased to 13.4 % at 5 ED. The value increased steadily over time, which is probably due to the achievement of steady state and the increasing age of the children (10 ED: 14.1 %, 15 ED: 15.5 %, 20 ED: 14.3 %, 70 ED: 14.7 %, 148 ED: 17.1 %). [4]

About the paradigm™ clinical trial program

The paradigm™ clinical trial program includes various studies [2-4,8-13] that evaluated the safety, efficacy, pharmacokinetic profile and immunogenicity of Refixia® in adult and pediatric populations. The use of Refixia® for the prophylaxis and emergency treatment of bleeding as well as during surgical procedures was tested. It is the longest study program of an EHL product. A non-interventional observational study on the safety of Refixia® is also ongoing.

literature
1 Refixia® specialist information, as of: August 2023
2 Carcao M et al. J Thromb Haemost 2016; 14: 1521-1529
3 Carcao M et al. Thromb Haemost 2020; 120:737-746
4 Chan AK et al. Res Pract Thromb Haemost 2020; 4:1101-1113
5 World Federation of Hemophilia (WFH). Guidelines for the management of hemophilia.
https://guidelines.wfh.org/chapter/prophylaxis-in-hemophilia/ (last accessed: June 12, 2023)
6 Mancuso ME, Santagostino E, J Clin Med. 2017; 6(4): 39
7 Mahlangu JN. Ther Adv Hematol 2018; 9:335-346
8 Collins PW et al. Blood 2014; 124:3880-3886
9 Negrier C et al. Blood 2011; 118(10): 2695-2701
10 Collins PW et al. J Thromb Haemost 2012; 10:2305-2312
11 Escobar MA et al. Haemophilia 2017; 23:67-76
12 Young G et al. Thromb Res 2016;141: 69-76
13 Escuriola Ettingshausen C et al. Res Pract Thromb Haemost 2019; 3:268-276