key: cord-0835465-34d6qc9b authors: Matino, Davide; Iorio, Alfonso; Keepanasseril, Arun; Germini, Federico; Caillaud, Alexandre; Carcao, Manuel; Hews‐Girard, Julia; Iserman, Emma; James, Paula; Lee, Adrienne; Phua, Chai W.; Sun, Haowei (Linda); Teitel, Jerome; Poon, Man‐Chiu title: Switching to nonacog beta pegol in hemophilia B: Outcomes from a Canadian real‐world, multicenter, retrospective study date: 2022-03-31 journal: Res Pract Thromb Haemost DOI: 10.1002/rth2.12661 sha: affb5f0101b3738b3b51dfb30c50ef23f6fdde38 doc_id: 835465 cord_uid: 34d6qc9b BACKGROUND: The Canadian Bleeding Disorders Registry (CBDR) captures data from 24 hemophilia treatment centers and patients directly. Nonacog beta pegol (N9‐GP) was approved in Canada in 2018. OBJECTIVES: To assess treatment outcomes following switching to N9‐GP in a real‐world setting. METHODS: CBDR data for Canadian male patients (aged 7–72 years) with hemophilia B receiving prophylactic N9‐GP for ≥6 months as of March 31, 2021, were included. To allow comparison with the previously used products, only patients for whom data were available in the CBDR for at least 6 months before the switch to N9‐GP were included in this retrospective analysis. RESULTS: Forty‐two patients were included in the analysis (total observation period: 148.0 patient‐years). The distribution of disease severity was 62% severe, 36% moderate, 2% mild, with 62% of patients previously receiving recombinant factor IX‐Fc‐fusion protein (rFIXFc) and 38% previously receiving standard half‐life (SHL) recombinant factor IX (rFIX). During a median follow‐up period of 2.3 years on N9‐GP prophylaxis, 232 bleeds were reported in 30 patients, 29% of patients reported zero bleeds. The median overall annualized bleeding rate on N9‐GP was 0.73 for patients switching from rFIXFc (previously 1.44) and 2.10 for patients switching from SHL rFIX (previously 6.06). Median total annualized factor consumption (IU/kg) was lower with N9‐GP than with previous SHL rFIX (2152 vs 3018) and previous rFIXFc (1766 vs 2278). CONCLUSIONS: Results from this first real‐world study of N9‐GP in patients with hemophilia B suggest optimal bleeding control with low factor consumption after switching to N9‐GP, irrespective of the previous product. • Real-world study of 42 patients in Canada switching to nonacog beta pegol (N9-GP) prophylaxis. • N9-GP treatment was compared with previously used products (standard half-life rFIX and rFIXFc). • Post-switch to N9-GP (follow-up 2.3 years), patients experienced lower annualized bleeding rates. • Annualized factor consumption for prophylaxis and for treatment of bleeds was reduced with N9-GP. Prophylaxis with coagulation factor IX (FIX) is recommended for patients with severe hemophilia B and for those with nonsevere hemophilia B with a severe bleeding phenotype. 1 show improved pharmacokinetics over SHL FIX, there are considerable differences in their pharmacokinetic profiles. [4] [5] [6] N9-GP is a site-specific glycoPEGylated EHL rFIX product that has demonstrated safety and efficacy in patients of all age groups in the paradigm clinical development program. 4, [7] [8] [9] [10] [11] This program focused on patients with moderate-to-severe hemophilia B who received defined dosing regimens for routine prophylaxis and treatment of bleeding episodes. There are currently no data on the clinical and economic outcomes of using N9-GP in a realworld setting. Additionally, there are no data on the real-world patterns of using N9-GP in clinical practice or on the outcomes after switching to N9-GP from a SHL FIX product or another EHL rFIX product. In Canada, real-world data for patients with hemophilia, including clinical outcomes and consumption rates of clotting factor concentrates, are recorded in the Canadian Bleeding Disorders Registry (CBDR) by both hemophilia treatment centers (HTCs) and patients. FIX products for patients with hemophilia B are subject to national competitive procurement processes in Canada, administered by the Canadian Blood Service (CBS) and Héma-Québec. 12 As a result of a tender, rFIXFc was the only EHL FIX available to patients from 2016 to 2018. In 2018, N9-GP was awarded a CBS contract and subsequently made available to patients across Canada (except Québec) beginning April 1, 2018. 13 Patients already receiving the EHL product rFIXFc were offered the opportunity to switch to either N9-GP or the SHL product rFIX because rFIXFc was no longer available for adult patients through CBS after April 1, 2018. Patients previously on SHL rFIX and plasma-derived FIX were also able to switch to N9-GP. Recombinant FIX albumin fusion protein, although approved by Health Canada, has never been made available in the inventory of the CBS or Héma-Québec. Currently, N9-GP is approved in Canada and reimbursed in all provinces except Québec, for routine prophylaxis in patients aged 18 years or older. It is also approved for use in pediatric patients for treatment of bleeds or prevention of bleeding in surgical settings, but not for routine prophylaxis. Despite this, the CBDR has recorded patients ≤18 years old receiving N9-GP prophylactically off-label. It is not unusual for pediatric patients to receive medications offlabel because medications are often licensed in adults before being licensed in children. To increase the sample size and generalizability of the study findings, these pediatric patients have been included in the analysis. Hence, this study aimed to use the change in the CBS contract to assess treatment outcomes for patients who switched from a prophylaxis regimen with either SHL rFIX or rFIXFc to a prophylaxis regimen with N9-GP in a real-world setting. prophylaxis, 232 bleeds were reported in 30 patients, 29% of patients reported zero bleeds. The median overall annualized bleeding rate on N9-GP was 0.73 for patients switching from rFIXFc (previously 1.44) and 2.10 for patients switching from SHL rFIX (previously 6.06). Median total annualized factor consumption (IU/kg) was lower with N9-GP than with previous SHL rFIX (2152 vs 3018) and previous rFIXFc (1766 vs 2278). Results from this first real-world study of N9-GP in patients with hemophilia B suggest optimal bleeding control with low factor consumption after switching to N9-GP, irrespective of the previous product. Canada, hemophilia B, N9-GP, nonacog beta pegol, prophylaxis, real-world 2 | ME THODS This was a retrospective study of Canadian patients with hemophilia B receiving prophylactic N9-GP for at least 6 months after switching from an earlier treatment product. The study was initiated on April 1, 2018, and data were collected until March 31, 2021, through the CBDR database, which records data from 24 HTCs and directly from patients. Eleven of the 24 HTCs contributed data for the purposes of this analysis (list of centers in Supplementary material 1). This preplanned readout occurred 2 years after study initiation. Patients of any age with hemophilia B of any severity treated with prophylactic N9-GP for ≥6 months were included in the study. For the comparison with previously used products, only patients treated prophylactically and for whom data existed in the CBDR for ≥6 months before the switch to N9-GP were included. The primary endpoints of this study were: a. N9-GP effectiveness for prophylaxis, described by annualized bleeding rate (ABR), annualized spontaneous bleeding rate (AsBR), annualized joint bleeding rate (AjBR), bleeding frequency in target joints (International Society on Thrombosis and Haemostasis [ISTH] definition: at least three spontaneous bleeds into a single joint in a 6-month period), 14 hemophilia joint health score (HJHS), and target joint progression (ISTH definition of target joint declassification: two or fewer bleeds into the joint within a consecutive 12-month period). 14 Only bleeds that required treatment were recorded in the CBDR database. b. Total overall annualized consumption and annualized consumption for prophylaxis. c. N9-GP consumption for surgery, described in terms of total factor consumption during surgery. The secondary endpoints of this study were: a. Change in ABR, AsBR, AjBR, bleeding frequency in target joints, HJHS, number of target joints, target joint progression, and number of infusions required to treat a bleeding episode, from previous FIX product to prophylaxis with N9-GP. b. Adherence to prophylaxis, described by the number of prophylactic infusions received compared with the number of prophylactic infusions prescribed. The exploratory endpoints of this study describe the number and frequency of adverse events for patients receiving N9-GP. To compare intrapatient bleed rates pre-and postswitching to N9-GP a negative binomial (NB) regression analysis was performed for each of the study groups, prior SHL rFIX, and prior rFIXFc, respectively. Estimated mean ABRs (95% confidence intervals [CIs]) before and after switching to N9-GP and corresponding rate ratio (RR) (95% CIs) were tabulated for each study group. Further, to compare intrapatient recurrent bleeding incidents between pre-N9-GP treatment and N9-GP, a shared frailty gamma model was fitted to the data for each of the study groups. 15 Estimated hazard ratios (HRs; 95% CIs, p values) of bleeding incidents comparing N9-GP with pre-N9-GP treatment were reported. Patient demographic data are presented in Table 1 Before switching to N9-GP, 26 (62%) patients received rFIXFc, F I G U R E 1 Flow diagram of patients from the CBDR included in the analyses. CBDR, Canadian Bleeding Disorders Registry; N9-GP, nonacog beta pegol. a As primary prophylaxis. b Includes one patient who received N9-GP on-demand before receiving prophylaxis for ≥3 months. c Includes one patient who received two products during the pre-switch period, and two patients who switched from an experimental medication Overall median (IQR) ABR for patients switching to N9-GP prophylaxis from rFIXFc was 0.73 (0.00-1.78) bleeds/patient/year compared with 1.44 (0.40-2.95) when previously receiving rFIXFc ( Figure 2) ; similarly, for patients who switched to N9-GP from SHL rFIX median (IQR), ABR was 2.10 (0.51-4.29) bleeds/patient/year compared with 6.06 (0.83-9.80) before switching ( Figure 2 ). Median (IQR) and mean (CI) ABR, AsBR, and AjBR before and after switching to N9-GP are presented in Figure 2 and Table 2 Over the follow-up period, there were 232 breakthrough bleeds reported in 30 (71%) patients while on N9-GP prophylaxis ( Table 2) . There were 17 surgeries recorded while patients were receiving N9-GP, with a median (range) factor consumption during the 14-day postoperative period of 84.5 (0.0-763.0) IU/kg (Table 4 ). No adverse events were recorded in the CBDR over the course of the analysis period. When patients ≥18 years old were analyzed separately, findings were consistent with the total study population (Supplementary material 3). Overall, the data collected from the CBDR showed a lower median ABR after switching to N9-GP compared with either previous SHL rFIX or rFIXFc, although a statistically significant reduction could be shown only for patients switching from SHL rFIX. The reduction in overall ABR was observed despite a drop in the median annualized factor consump- The annualized number of recorded prophylactic infusions was lower with N9-GP than with both SHL rFIX and rFIXFc, despite being prescribed at the same infusion frequency as rFIXFc. This may suggest improvement in symptoms of hemophilic arthropathy after switching to N9-GP. In fact, four patients reported resolution of target joints following a switch from SHL rFIX to N9-GP, and two patients reported resolution of target joints in those who switched from rFIXFc. Some bleeds were still reported in patients receiving N9-GP prophylaxis. Given that the median patient age for this study was 42 years, many patients are likely to have had preexisting joint damage or target joints, which may have contributed to them continuing to report breakthrough bleeds after switching to N9-GP prophylaxis. Following the switch from SHL rFIX to N9-GP, most bleeds (90.2%) required only one infusion to achieve hemostasis compared with 73.2% of bleeds on SHL rFIX requiring one infusion. The proportion of bleeds treated with only one infusion remained stable (72% vs 71%) following the switch from rFIXFc to N9-GP. The finding that >90% of bleeds treated with N9-GP needed only one infusion of N9-GP to achieve hemostasis is consistent with the hemostatic efficacy observed in the paradigm trials with N9-GP (40 IU/kg once weekly). 4, 7, 9, 17 Interestingly, ABR outcomes were lower in the cohort that switched to N9-GP from rFIXFc than in the cohort that switched to N9-GP from SHL rFIX. Over time, with further follow-up on N9-GP, these rates may become more similar; in fact, when comparing the outcomes reported at this 2-year readout with those previously reported at the earlier 1-year readout, 15 a decrease is observed across all ABR measures. The analysis of intrapatient bleeding rates allowed for effective comparison of ABR despite the imbalance in follow-up periods, the robustness of these findings was confirmed by using both the NB regression and shared frailty gamma models. The improvements in ABR and consumption outcomes observed after switching from rFIXFc to N9-GP might be due to the high trough levels observed between doses of N9-GP, which may in turn confer a protective effect. 18 Additionally, adherence to prophylactic SHL rFIX appeared lower than with either rFIX-Fc or N9-GP. The effects of more consistent prophylaxis may not fully manifest until years after switching to an EHL product. Because the switch from rFIXFc was due to the product no longer being provided under the CBS contract (though still available via Health Canada's special access program) rather than because of inadequate disease control, the 1.35-year follow-up period was likely representative of the overall patient experience on rFIXFc. However, because access to SHL rFIX was unaffected by CBS contracting changes, the patients who switched from SHL rFIX may be a selfselected group whose disease was not adequately controlled by their prior treatment. Given the small sample size and self-reporting nature of this retrospective study, insufficient data were available to report on all the planned endpoints set out in the study protocol. However, it is anticipated that sufficient data will be available to report on these additional endpoints at subsequent data readouts. The small sample size is the main limitation of this study. This limitation is common among hemophilia B studies given the rarity of the disease. Additionally, CBDR data are collected as part of routine clinical practice, and therefore data are not always optimally complete or standardized; this was further compounded by the COVID-19 pandemic in 2020, which limited attendance at hemophilia clinics for physical examinations. For example, for the endpoint HJHS, insufficient data were available (4/42 patients) to power a meaningful analysis. Because the study was retrospective and non-interventional, it was not possible to audit patients for their data entry activity for the purposes of the study. According to the CBDR's standard data quality improvement initiative, investigators were able to encourage the HTCs and their patients to be as compliant as possible when entering data into CBDR, but the data collection activity remained completely voluntary. In summary, this study provided the first report of the efficacy and safety of N9-GP in a real-world setting. The results of this study suggest that N9-GP compares favorably with both SHL rFIX and rFIXFc in terms of improved bleeding outcomes and reduced rFIX consumption. The has received research support from Bayer, Bioverativ/Sanofi, and Pfizer; and honoraria for speaking/participating in advisory boards from Bayer .'s institution has received research support from BioMarin, CSL, Freeline, Grifols, Novo Nordisk, Octapharma, Sanofi, Spark, and Uniqure. A.C. is an employee of Novo Nordisk Novo Nordisk, Octapharma, Pfizer, and Shire/Takeda and honoraria for speaking/participating in advisory boards from Bayer has received research support from Bayer and Novo Nordisk Novo Nordisk, Pfizer, and Shire/Takeda; ad hoc speaker for Bayer, Novo Nordisk, and Pfizer; attended advisory board meetings of Bioverativ/Sanofi, CSL Behring, Novo Nordisk, Pfizer, Roche, and Takeda; and received grant funding from Bayer and CSL Behring has received honoraria for participating in advisory boards and travel support from Alexion has received honoraria for participating in advisory boards from Novo Nordisk, Octapharma, and Sanofi and research support from has received grant funding from Bayer and CSL Behring; ad hoc speaker for Bayer, Novo Nordisk, and Pfizer Guidelines for the management of hemophilia Updates in clinical trial data of extended half-life recombinant factor IX products for the treatment of haemophilia B Outcome of clinical trials with new extended half-life FVIII/IX concentrates Nonacog beta pegol (N9-GP) in haemophilia B: a multinational phase III safety and efficacy extension trial (paradigm4) Long-acting recombinant coagulation factor IX albumin fusion protein (rIX-FP) in hemophilia B: results of a phase 3 trial Phase 3 study of recombinant factor IX Fc fusion protein in hemophilia B Recombinant long-acting gly-coPEGylated factor IX in hemophilia B: a multinational randomized phase 3 trial Enhanced pharmacokinetic properties of a glycoPEGylated recombinant factor IX: a first human dose trial in patients with hemophilia B Nonacog beta pegol in previously treated children with hemophilia B: results from an international open-label phase 3 trial Low-factor consumption for major surgery in haemophilia B with long-acting recombinant glycoPEGylated factor IX Nonacog beta pegol (N9-GP) in hemophilia B: first report on safety and efficacy in previously untreated and minimally treated patients Guide to National Tenders for the Purchase of Clotting Factor Concentrates CBS contracts for FVIII and FIX for 2018-2020 Definitions in hemophilia: communication from the SSC of the ISTH Modelling recurrent events: a tutorial for analysis in epidemiology Canadian, multicenter, retrospective, non-interventional study of clinical outcomes from early use of N9-GP compared with previous treatment in patients with hemophilia B in a real-world setting Nonacog beta pegol (N9-GP) in hemophilia B: first report on safety and efficacy in previously untreated and minimally treated patients Once-weekly prophylaxis with 40 IU/kg nonacog beta pegol (N9-GP) achieves trough levels of >15% in patients with haemophilia B: pooled data from the para-digm™ trials All authors made substantial contributions to conception and design, acquisition of data, or analysis and interpretation of data; took part in drafting the article or revising it critically for important intellectual content; gave final approval of the version to be published; and agree to be accountable for all aspects of the work. https://orcid.org/0000-0002-3331-8766Federico Germini https://orcid.org/0000-0002-0802-3616Paula James https://orcid.org/0000-0003-4649-9014Haowei (Linda) Sun https://orcid.org/0000-0002-0205-9722Jerome Teitel https://orcid.org/0000-0001-6455-8167