The therapeutic efficacy of nonacog beta pegol in the prophylaxis and on-demand treatment of bleeding episodes in previously treated patients aged 13–70 years with haemophilia B was evaluated in the pivotal, randomized, single-blind, phase 3 Paradigm 2 trial . The use of nonacog beta pegol in maintaining perioperative haemostasis in this patient population was investigated in the open-label, single-arm, phase 3 Paradigm 3 trial . Patients completing either Paradigm 2 or Paradigm 3 trial were subsequently enrolled in the nonrandomized, open-label extension Paradigm 4 trial . The efficacy and safety of nonacog beta pegol was also assessed in previously treated paediatric patients aged 0–12 years in the phase 3 Paradigm 5 trial , which is briefly discussed in this review as nonacog beta pegol is not indicated for children aged < 12 years in the EU (Sect. 6).
The Paradigm 2  and Paradigm 3  trials included males with haemophilia B (FIX activity ≤ 0.02 IU/mL), with a history of ≥ 150 exposure days to other FIX products. Exclusion criteria included current or historical presence of FIX inhibitors (i.e. FIX neutralizing IgG antibodies), HIV infection with a CD4 lymphocyte count of ≤ 200 cells/µL and a history of thromboembolic events [8, 14]. Paradigm 2 also excluded patients receiving immunomodulating or chemotherapeutic drugs and those with a platelet count of < 50,000/μL, an ALT level of > 3 times the upper limit of normal (ULN) or a creatinine level of ≥ 1.5 times the ULN .
Prophylaxis and On-demand Treatment
In Paradigm 2, patients were randomized to prophylaxis with nonacog beta pegol 10 or 40 IU/kg once weekly for 52 weeks; an additional nonrandomized treatment group received on-demand nonacog beta pegol treatment for 28 weeks . Patients could choose between prophylaxis and on-demand treatment. Bleeding episodes in all three treatment groups were treated with a single nonacog beta pegol dose of 40 IU/kg (80 IU/kg if bleeding was severe, i.e. intracranial, iliopsoas, neck or retroperitoneal bleeding). The main efficacy endpoints were the haemostatic effect when treating a bleeding episode, assessed by patient-rated haemostatic response as defined in Table 2, and the prophylactic effect, assessed by annualized bleeding rate (ABRs) during the trial (Table 3) . In the EU, 10 IU/kg is below the recommended dosage of 40 IU/kg (Sect. 6), but is discussed in this review for comparison and completeness.
Paradigm 2 enrolled 74 patients (mean age 31.4 years), with 67 patients completing the trial, including 17 adolescents (13–17 years) and 50 adults (18–65 years) . Of the 74 patients, 19 and 81% had moderate and severe haemophilia B, respectively, and approximately one-half had previously received FIX products on-demand (47%) or as prophylaxis (53%). Among those who had received prophylaxis (n = 39), 54 and 46% of patients had received rFIX and pdFIX, respectively. At baseline, 65% of patients had arthropathy and 54% had target joints . A target joint was defined, according to the European Paediatric Network for Haemophilia Management (PEDNET), as ≥ 3 bleeds in a particular joint within a period of 6 months before trial, regardless of the causality of the bleed (i.e. spontaneous or traumatic) [8, 20].
Paradigm 4 was planned for an additional 50 exposure days to nonacog beta pegol to that received in Paradigm 2 . It enrolled 71 patients, 66 from Paradigm 2 and five from Paradigm 3 (Sect. 4.2). Initially, Paradigm 4 had the same three treatment groups as in Paradigm 2: i.e. two prophylaxis groups (10 or 40 IU/kg once-weekly) and an on-demand group, with bleeds in all groups treated with a single 40 IU/kg (80 IU/kg for severe bleeds) dose. In addition, a third prophylaxis group (80 IU/kg every second week) was included following a late trial protocol amendment, although only two patients received this regimen, as the trial was stopped soon after the amendment. The patient and investigator selected the treatment group at trial entry and the patients were allowed to change treatment groups during the trial based on clinical manifestations and investigator’s recommendations. At trial entry, 20 patients changed their treatment groups from their original group in Paradigm 2 and nine patients changed treatment groups during the trial .
Paradigm 5 enrolled 25 paediatric patients who received prophylaxis with nonacog beta pegol 40 IU/kg once weekly for 52 weeks during the trial . Patients experiencing breakthrough bleeds received a single nonacog beta pegol dose of 40 IU/kg for mild to moderate bleeds or 80 IU/kg for severe bleeds .
On-demand treatment with nonacog beta pegol 40 IU/kg (80 IU/kg for severe bleeding) was effective in treating bleeding episodes in patients with haemophilia B [8, 15, 19, 20]. Bleeding and haemostatic response data for all patients and individual treatment groups in the Paradigm 2 and 4 trials are summarized in Table 2 [8, 15]. In Paradigm 2, a total of 345 bleeding episodes (202 in the prophylaxis groups and 143 in the on-demand group) were treated with nonacog beta pegol, with an estimated successful haemostatic response rate of 92.2% (95% CI 86.9–95.4) . The success rate was the highest in the 40 IU/kg prophylaxis group, with 99% of bleeding episodes stopped with one injection (Table 2) . There was one severe bleeding episode (in the knee joint) in the 10 IU/kg group, which was treated with nonacog beta pegol 80 IU/kg, with the haemostatic response rated as excellent . In Paradigm 4, a total of 207 bleeding episodes were treated with nonacog beta pegol, with a successful haemostatic response rate of ≈ 95% (Table 2) . No severe bleeding episodes were reported during the trial .
According to a post hoc analysis of Paradigm 2, nonacog beta pegol was effective in treating target joint bleeds . At baseline, 13 and 15 patients in the 10 and 40 IU/kg prophylaxis groups had at least one target joint. During the trial, there were 49 and 19 breakthrough target joint bleeds requiring treatment, respectively, with 78 and 100% of these bleeds resolving with one nonacog beta pegol 40 IU/kg injection. The successful haemostatic response rate was 81 and 95% in the 10 and 40 IU/kg groups .
In Paradigm 5, 42 breakthrough bleeds occurred in 15 of 25 (60%) patients . In these patients, on-demand treatment was associated with an overall successful haemostatic response rate of 92.9%, with 86% of bleeds resolving with one injection .
In Paradigm 2, nonacog beta pegol 40 IU/kg once weekly prophylaxis effectively reduced ABRs in patients with haemophilia B [8, 20]. In patients not receiving prophylaxis (i.e. on-demand treatment group) the median ABR was 15.58 , whereas it was 1.04 and 2.93 in the 40 and 10 IU/kg prophylaxis groups (Table 3) . Although both prophylaxis regimens reduced the estimated mean ABRs, the predefined criteria for the effective prophylaxis in the overall population was met only in the 40 IU/kg group but not in the 10 IU/kg group (Table 3). FIX activity levels were sustained throughout the prophylaxis dosing intervals; the estimated mean spontaneous ABRs were only slightly higher towards the end of the intervals (1.87 during the first 4 days and 2.16 after 4 days of the previous administration) . The prophylactic efficacy was also evident with respect to the proportion of patients who did not have a bleeding requiring treatment: 45 and 17% in the 40 and 10 IU/kg prophylaxis groups (Table 3), compared with 7% in the on-demand group .
Consistent with the overall population, in a subgroup of patients who entered the Paradigm 2 trial from a previous prophylaxis regimen, the prophylactic effect of nonacog beta pegol was more pronounced in the 40 IU/kg group (the estimated mean ABR decreased from 7.49 in the 12 months prior the trial to 3.33 during the trial) than in the 10 IU/kg group (5.13 to 4.68) . In patients who entered the trial from previous on-demand treatment, the corresponding changes were 21.2 to 1.3 in the 40 IU/kg group and 17.9 to 4.3 in the 10 IU/kg group .
In Paradigm 2, the 40 IU/kg regimen was also more effective than the 10 IU/kg regimen in patients with target joints [8, 20]. Using the PEDNET definition of a target joint, 15 and 13 patients in the 40 and 10 IU/kg prophylaxis groups had at least one target joint at trial entry, with each group having 24 target joints among them. Of these patients, 66.7 and 7.7% of patients in the 40 and 10 IU/kg groups did not have a bleeding requiring treatment in their target joints during the trial [8, 20]. Furthermore, in the post hoc analysis, 71 and 29% of target joints at baseline in the respective groups had no bleeding during the trial . The median ABR [interquartile range (IQR)] in target joints during the trial was 0.0 (0.00–2.01) in the 40 IU/kg group and 2.59 (1.85–5.22) the 10 IU/kg group . The corresponding estimated mean ABRs (95% CI) were 1.32 (0.35–5.05) and 4.10 (2.59–6.51), respectively . The prophylactic efficacy of the 40 IU/kg regimen in patients with target joints was further supported by the post hoc analysis  when the most recent definition of a target joint from the International Society on Thrombosis and Haemostasis  was used.
Paradigm 4 results showed that long-term prophylaxis with nonacog beta pegol remained effective in patients with haemophilia B . Among patients who remained on the same treatment group for ≥ 3 months (n = 66), 125 bleeds were reported in 43 patients. The median ABR in these patients was ≈ 1 (Table 3). In Paradigm 4, ABRs in the 40 IU/kg group were low and similar to that seen in Paradigm 2. However, the difference between the 40 and 10 IU/kg groups in ABR and the number of patients without bleeds was diminished in Paradigm 4 relative to Paradigm 2 (Table 3), which may be attributed to the differences in the trial designs (Sect. 4.1) .
Twelve patients had low estimated mean ABRs (1.26) with the nonacog beta pegol 10 IU/kg regimen in Paradigm 2 and continued this regimen in Paradigm 4 during which the ABR slightly increased to 1.97 . Fourteen patients had high estimated mean ABRs (6.89) with the 10 IU/kg regimen in Paradigm 2 and switched to the 40 IU/kg regimen in Paradigm 4; in these patients, ABR decreased to 2.78 during Paradigm 4. In 22 patients who remained on the 40 IU/kg regimen throughout both trials, the estimated mean ABRs were 2.29 and 1.16 during Paradigm 2 and Paradigm 4, respectively .
In Paradigm 5, the median ABR was 1.0 (IQR 0.00–2.06) and the median spontaneous ABR was 0.00 in children receiving nonacog beta pegol prophylaxis [12, 19].
Health-Related Quality of Life
Nonacog beta pegol 40 IU/kg once-weekly prophylaxis was associated with improvements in HR-QOL in patients with haemophilia B, as assessed by patient-reported outcome questionnaires in Paradigm 2 and 4 [8, 22]. In Paradigm 2, adult patients (≥ 17 years of age) receiving the 40 IU/kg regimen had significant (p ≤ 0.031) improvements from baseline in Haemophilia Quality Of Life Questionnaire For Adults (Haem-A-QoL) total score and scores for certain domains therein (sport, feeling, partnership) at the end of trial; no significant changes were seen in the 10 IU/kg prophylaxis or on-demand treatment groups . In Paradigm 4, adult patients who switched from 10 to 40 IU/kg group had significant (p = 0.016) improvements from baseline in Haem-A-QoL total scores and physical health domain score. In adolescent patients (13–16 years of age) receiving nonacog beta pegol prophylaxis, there were no significant changes from baseline in HR-QOL parameters as assessed by the Haemophilia Quality Of Life Questionnaire For Children (Haemo-QOL) III, according to limited data from Paradigm 2 (n = 15) and Paradigm 4 (n = 12) .
In Paradigm 2, patients receiving 40 IU/kg prophylaxis reported a significant (p = 0.030) improvement from baseline in their global health status on a EQ-5D visual analogue scale, while there was no significant change in the 10 IU/kg prophylaxis or on-demand treatment groups . Patients reported on EQ-5D that mobility and pain/discomfort as the main problems over the course of Paradigm 2. In the 40 IU/kg group, the proportion of patients having ‘some problem’ with mobility decreased from 51.7% at baseline to 20.7% at the end of the trial. The corresponding change in patients with ‘moderate or extreme’ pain/discomfort was 44.8 to 27.6%. Nonacog beta pegol was also associated with a significant (p = 0.016) improvement from baseline in the three-level version of the EQ-5D index score (using the UK value set) in the overall population in Paradigm 2, with no significant differences observed in individual treatment groups .
Paradigm 3 enrolled 13 patients with haemophilia B scheduled for a major surgery (nine orthopaedic, three dental and one gastrointestinal procedures), including seven patients transferred from Paradigm 2 or Paradigm 4 and six new patients naive to nonacog beta pegol .
At trial entry, naive patients received two 40 IU/kg dosages (separated by 4–8 days) to assess hypersensitivity or anaphylactic reactions and to calculate in vivo recovery; transferred patients who had been receiving 10 IU/kg once weekly or on-demand treatment regimen received a single 40 IU/kg dose to calculate in vivo recovery, while recovery data for patients who had been receiving 40 IU/kg once-weekly was obtained from the preceding trial . During the preoperative period, patients coming from a prophylaxis regimen received 40 IU/kg once weekly while those coming from an on-demand regimen received 40 IU/kg every 7–14 days. Preoperative treatment was continued for 2–8 weeks (naive patients) or 2–4 weeks (transferred patients). On the day of surgery (≥ 7 days from the last dose of nonacog beta pegol), all patients received a single bolus injection 80 IU/kg within 4 h prior to the procedure. Postoperatively, fixed doses of 40 IU/kg were administered at the discretion of the investigator to maintain FIX levels of 0.4–0.6, 0.3–0.5 and 0.2–0.4 IU/mL during days 1–3, 4–6 and 7–14, respectively .
In Paradigm 3, preoperative prophylaxis followed by a single presurgical nonacog beta pegol dose of 80 IU/kg was effective in maintaining the intraoperative haemostasis in patients undergoing a major surgery . In all 13 cases, this outcome was rated as excellent (10 cases) or good (3 cases) by the investigator/surgeon, according to a predefined response scale. None of the patients required additional doses on the day of surgery. A median of two and three injections were administered during postoperative days 1–6 and 1–13, respectively. The mean total consumption of nonacog beta pegol during and after surgery was 241.2 IU/kg .