A Retrospective Observational Study of Rurioctocog Alfa Pegol in Clinical Practice in the United States

BACKGROUND: Research describing patient experience and outcomes with extended half-life recombinant factor VIII (EHL rFVIII) outside of clinical trials is limited. Real-world rFVIII consumption studies, when people with hemophilia A (PWHA) switch from standard half-life (SHL) to EHL rFVIII, may help payers and clinicians make more informed treatment choices. OBJECTIVE: To conduct a retrospective, observational, U.S.-based analysis to describe clinical and demographic profiles of PWHA who switched to prophylactic rurioctocog alfa pegol. METHODS: Data were obtained from PWHA treated by 38 prescribers across 21 states using specialty pharmacy database case report forms, electronic medical records, and direct communication with providers, PWHA, or their guardians. Assessments included disease severity, pain severity, number and location of target joints, prior HA therapy, reasons for switching, treatment duration, dosing frequency, adherence, and annualized bleeding rates (ABRs) before and after switching to rurioctocog alfa pegol from SHL or another EHL rFVIII. RESULTS: Data were collected from 56 PWHA. The mean age was 26 years (range = 5-88); median age was 24 years (interquartile range = 14-34); 20% were aged < 12 years; and 89% (50/56) had severe HA. All PWHA had ≥ 12 months of rFVIII treatment before switching to rurioctocog alfa pegol. The population had a mean 1.8 target joints. Baseline subjective pain assessment was mild to moderate for 68% (38/56) of respondents. Before receiving rurioctocog alfa pegol, most PWHA received antihemophilic factor (recombinant) for prophylaxis (73%, 41/56) or breakthrough bleeding (59%, 33/56). Mean dosing frequency for prior prophylaxis was 2.8 per week for SHL rFVIII and 1.8 per week for EHL rFVIII, and 2.2 per week for all PWHA after switching to rurioctocog alfa pegol prophylaxis. The median time on rurioctocog alfa pegol prophylaxis was 12.0 months versus 80.8 months on previous SHL rFVIII and 13.5 months on previous EHL rFVIII. Mean ABRs on prior prophylaxis were 5.9 for SHL rFVIII (n = 35) and 4.7 for EHL rFVIII (n = 3). After switching to rurioctocog alfa pegol, the overall mean ABR reduced by 71% (5.8 to 1.7, P < 0.001) and 20/56 PWHA had no bleeding events. There was also a 20.9% reduction in the mean days per week of factor administration (P < 0.001) after switching to prophylactic rurioctocog alfa pegol. For 47 PWHA who switched from SHL rFVIII, their weekly dose decreased from 109.8 to 100.6 IU per kg with rurioctocog alfa pegol (P = 0.094). The proportion of PWHA with good/complete treatment adherence increased from 68% (38/56) on any prior rFVIII to 80% (45/56) on rurioctocog alfa pegol. The most common reason PWHA switched to rurioctocog alfa pegol was to reduce treatment infusions. CONCLUSIONS: Switching from either an SHL or EHL rFVIII to rurioctocog alfa pegol is associated with fewer bleeding episodes owing to more effective prophylaxis and improved adherence. Those who switched from an SHL rFVIII reported reduced factor consumption with rurioctocog alfa pegol. This long-acting factor is an important additional option for the care of PWHA.

H emophilia A (HA) is an X-linked congenital bleeding disorder caused by deficient or defective coagulation factor VIII (FVIII). 1 The predominant clinical characteristic of HA is repeated bleeding episodes, which cause acute or long-term threats to health including chronic joint disease. These effects reduce the patient's health-related quality of life. 2 As the primary aim of HA management is to prevent bleeding episodes, the current standard of HA care is prophylactic replacement treatment with recombinant FVIII (rFVIII) concentrates. 3,4 The half-lives of standard half-life (SHL) rFVIII products are ~10-14 hours, requiring intravenous infusion every other day or 3 days per week. 5,6 Patient survey data suggest that the time-consuming nature of prophylactic FVIII regimens is the most important barrier to treatment adherence in HA care. 7,8 In 2014, the first-generation extended half-life (EHL) rFVIII, Fc fusion protein (rFVIIIFc), received U.S. Food and Drug Administration approval for the treatment of HA. [9][10][11] With EHL rFVIII products becoming available for • The need for regular infusions with standard half-life recombinant factor VIII (SHL rFVIII) may have a high treatment burden on people with hemophilia A (PWHA) and their caregivers. • There is a paucity of research describing the patient experience and outcomes with extended half-life (EHL) rFVIII outside of clinical trials. • Real-world rFVIII consumption studies, when PWHA switch from SHL FVIII to rurioctocog alfa pegol, may assist with treatment decisions.

What is already known about this subject
• This is the largest study, outside of a clinical trial setting, that has assessed clinical profiles and rFVIII consumption among PWHA who switched to rurioctocog alfa pegol from an SHL or other EHL rFVIII therapy. • These real-world data indicate that switching from an SHL rFVIII to rurioctocog alfa pegol is associated with fewer bleeding episodes owing to more effective prophylaxis, and with reduced factor consumption and increased adherence. • This long-acting factor is an important additional option for the care of PWHA.

What this study adds
with rurioctocog alfa pegol, and 3 specialty pharmacies that serviced patients who met the study inclusion criteria were selected for analysis. Data were collected using specialty pharmacy database case report forms, electronic medical records, and standard data collection forms for completion by providers, clinicians, and PWHA or their guardians. Enrolled study clinicians and specialty pharmacies signed compliance agreements regarding the disclosure of patient information to the shared prescription database. PWHA or their guardians signed electronic informed consent forms designed by the Trio Health Advisory Group (La Jolla, CA).

Patients
Eligible PWHA had received previous treatment with a prophylactic rFVIII product for ≥ 12 months before switching to rurioctocog alfa pegol. PWHA were only eligible for the study if they had received the approved prophylaxis dosage regimen of rurioctocog alfa pegol during the course of the study, defined as 40-50 IU per kg body weight twice weekly. 13 Exclusion criteria were the participation in a rurioctocog alfa pegol clinical trial before or during the study period and the presence of FVIII inhibitory antibodies requiring treatment and/or the use of immune tolerance induction during the study period.

Assessments and Endpoints
Baseline patient characteristics collected included disease severity, prior HA therapy, number and location of target joints, level of pain (patients were asked to describe their pain levels on a scale of 1 to 5; 1 = mild pain, 5 = severe pain), and annualized bleeding rates (ABRs). ABRs for prior therapies were recorded as the number of bleeds in the 12 months before switching to rurioctocog alfa pegol. Measured endpoints before and after switching to rurioctocog alfa pegol included ABRs, months on therapy, and ordinal treatment adherence based on a subjective assessment by the PWHA (from prescriptions filled, 100% is complete adherence, 80%-99% is good adherence, 50%-79% is moderate adherence, and < 50% is poor adherence). Factor consumption was measured as the weekly exposure to FVIII (IU per kg). Frequency of treatment administration was assessed as weekly administrations of FVIII. For rurioctocog alfa pegol therapy, the ABR was only calculated if a PWHA had received rurioctocog alfa pegol for ≥ 3 months. Excluding patients with < 3 months of FVIII prophylaxis is a common approach to evaluating ABR in PWHA. 22 No safety data were collected for this analysis.
PWHA or their caregivers were asked to select their reasons for switching to rurioctocog alfa pegol from a list of 12 options; other user-defined reasons could also be stated. Patients could choose > 1 reason. people with hemophilia A (PWHA), fewer treatment infusions are needed (~2 infusions per week), so the burden of prophylactic rFVIII administration is reduced. 7 There is no uniform definition of an EHL rFVIII product, although an evidence-based review has proposed the defining characteristics to help clinicians and patients select the most appropriate rFVIII product. 12 Rurioctocog alfa pegol (Adynovate [U.S.]/Adynovi [Europe]; Baxalta U.S. Inc., a Takeda company, Lexington, MA) is a novel third-generation EHL rFVIII based on antihemophilic factor (recombinant) (Advate; Baxalta U.S. Inc., a Takeda company, Lexington, MA), with a modified polyethylene glycol A component. [13][14][15] This modification increases the half-life of the rFVIII by 1.4 to 1.5-fold compared with SHL rFVIII. 5,16 Since the introduction of first-generation EHL rFVIII, there has been an increase in clinical data supporting the use of EHL rFVIII for FVIII replacement treatment in PWHA. 12 However, publications of real-world outcomes data with EHL rFVIII such as rurioctocog alfa pegol are limited, 3 because of the relatively recent approval by the U.S. Food and Drug Administration and availability of EHL rFVIII products. 11,13,17,18 This represents a knowledge gap in the current understanding of the effect of EHL rFVIII on disease burden in the clinical practice setting.
A specific concern for payers is that real-world rFVIII consumption, by far the greatest lifetime cost input of HA, 7 may be different from that observed in clinical studies. This issue is highly pertinent when considering real-world use of EHL rFVIII, because recently published data on the financial cost of switching from an SHL to an EHL rFVIII show that, on average, EHL rFVIII products are more costly per patient per year (cost increase of 67.8%). 19 Compared with SHL rFVIII, the dose of EHL rFVIII is higher per infusion but with a reduced dosing frequency. As a result, although data from clinical trials indicate that overall consumption is similar for SHL and EHL rFVIII products, 20,21 there could still be concern among payers that the overall consumption of EHL rFVIII may be higher than SHL rFVIII. The clinical characteristics of PWHA who switch treatments, their reasons for switching treatments, and their health status as a result of switching to EHL rFVIII should be taken into account when considering overall rFVIII consumption.
This retrospective, observational, U.S.-based analysis was conducted to describe the clinical and demographic profiles of PWHA who switched from prophylaxis with any rFVIII product to prophylactic rurioctocog alfa pegol. In addition, the real-world consumption of rurioctocog alfa pegol and its relationship with clinical outcomes and treatment adherence were assessed.

■■ Methods Data Collection
A convenience sample of 120 specialty U.S. pharmacies were contacted; 17 indicated dispensing data for > 1 PWHA treated

Statistical Analyses
Continuous variables were assessed using paired 2-tailed t-tests, with P < 0.05 regarded as statistically significant. Categorical values were assessed using McNemar's test for case-controlled studies. Analyses were conducted overall and within subgroups stratified by prior prophylactic rFVIII product (SHL or EHL rFVIII) and age group (< 12 years, ≥ 12 years).

■■ Results Patient Flow and Characteristics
Data were collected from 56 eligible PWHA from November 2015 to September 2017 through 3 specialty pharmacies from 38 providers at 32 distinct practices across 21 states (Figure 1). Of the 56 PWHA receiving rurioctocog alfa pegol, 2 discontinued treatment before the end of data collection in September 2017 (1 following 3 months of rurioctocog alfa pegol therapy and another following 12 months of therapy). Complete information on dosing and infusion frequency was reported for 51 PWHA; this enabled comparison of rFVIII dosing and frequency before and after switching treatment.

Prior Prophylactic rFVIII Replacement Treatment and Reasons for Switching to Rurioctocog Alfa Pegol
The majority of PWHA received SHL rFVIII prophylaxis before switching to rurioctocog alfa pegol prophylaxis (93%; n = 52/56), and the remaining 4 patients (7%) received a different EHL rFVIII before switching ( Figure 2). Overall, 52 PWHA were treated for breakthrough bleeding while on prior SHL or EHL rFVIII prophylaxis; 85% (n = 44/52) of these PWHA received SHL rFVIII and 4 received EHL rFVIII for prior treatment of breakthrough bleeds. Antihemophilic factor (recombinant) was the most commonly administered rFVIII for prophylaxis and for the treatment of breakthrough bleeding.   Overall, the 3 most common reasons for switching from another rFVIII to rurioctocog alfa pegol were: 1) to reduce the number of infusions, 2) to reduce breakthrough bleeds, and 3) to improve treatment adherence ( Figure 3). PWHA aged ≥ 12 years (n = 45) had the same top 3 reasons for switching rFVIII as the overall population; however, for PWHA aged < 12 years (n = 11), venous access issues were the second most common reason for switching to prophylactic rurioctocog alfa pegol (after reducing the number of infusions [patient and caregiver] and before improving adherence and reducing breakthrough bleeds).

Real-World Consumption of Prophylactic Rurioctocog Alfa Pegol
Data for the consumption of prophylactic rFVIII were available for 51 of 56 PWHA (Table 2). Five PWHA were excluded from this analysis because they had incomplete information on dosing or frequency of rFVIII therapy before receiving rurioctocog alfa pegol.
After switching to rurioctocog alfa pegol, PWHA experienced a significant reduction of 20.9% in the mean number of days per week of factor administered (from 2.7 to 2.2, P < 0.001) in the overall population (Table 2). This reduction was significant for those PWHA who switched from an SHL rFVIII (23.1% reduction, P < 0.001), but not for PWHA who switched from   an EHL rFVIII (21.4% increase, P = 0.215), although the latter population comprised only 4 PWHA. There was no significant difference in the mean weekly rFVIII dose reported before and after switching to rurioctocog alfa pegol in the overall population or in the groups of PWHA who received prior treatment with an SHL or EHL rFVIII. The frequency of factor administration was comparable between the overall population and PWHA aged ≥ 12 years, who had a significant 22.4% reduction in the mean number of days per week of factor consumption after switching to rurioctocog alfa pegol (from 2.7 to 2.1, P = 0.001). The 14.3% reduction in the mean number of days per week of factor consumption after switching to rurioctocog alfa pegol in PWHA aged < 12 years is interpreted with caution given the small sample size (n = 9, P = 0.133).
Also, in line with the overall population, the reduction in the mean number of days per week of factor administration was significant for those PWHA aged ≥ 12 years who switched from an SHL rFVIII (25.2% reduction from 2.8 days per week to 2.1, P < 0.001), but not for those PWHA aged ≥ 12 years who switched from an EHL rFVIII (21.4% increase from 1.8 days per week to 2.1, P = 0.215). For PWHA aged < 12 years, such a comparison could not be made between those who received a previous SHL or EHL rFVIII because no PWHA aged < 12 years had received an EHL rFVIII before rurioctocog alfa pegol therapy.
Of the 38 PWHA with bleeding data before and after switching to rurioctocog alfa pegol, 33 were aged ≥ 12 years. In this subgroup, the mean ABR decreased from 6.0 to 1.7 after switching to
When assessed by prior rFVIII therapy, good-to-complete adherence was reported by 67% (n = 35/52) of all PWHA who received prior SHL rFVIII and 79% (n = 41/52) after they switched to rurioctocog alfa pegol. Good-to-complete adherence was reported by 3 of the 4 PWHA who received prior EHL rFVIII and all 4 PWHA after switching to rurioctocog alfa pegol. In the < 12 years age group overall, good-to-complete adherence was reported by 100% (n = 11/11) of PWHA who received prior SHL or EHL FVIII and 91% (n = 10/11) after they switched to rurioctocog alfa pegol. For the ≥ 12 years age group overall, good-to-complete adherence was reported by 60% (27/45) of PWHA who received prior SHL or EHL rFVIII and 78% (35/45) after they switched to rurioctocog alfa pegol.

■■ Discussion
This study represents the largest detailed evaluation of the realworld use of rurioctocog alfa pegol in PWHA following prior prophylaxis with other (SHL and EHL) rFVIII products. The effect of this switch in treatment on clinical outcomes (including ABR), treatment adherence, and factor consumption were all reported, along with the reasons for switching. A previous retrospective chart review had shown a general improvement in bleeding control in patients who switched from SHL rFVIII to rurioctocog alfa pegol, with a lower infusion frequency and factor consumption in most patients; this study evaluated data from 15 patients, none of whom were previously treated with EHL rFVIII. 23 The ongoing international AHEAD study (NCT02078427) is assessing the natural history of hemophilia A and long-term outcomes in terms of effectiveness, safety, and quality of life in patients receiving rFVIII or rurioctocog alfa pegol in routine clinical practice across more than 20 countries. 24 The reduction of ABR is the most important goal of prophylaxis in HA. Clinical study data have shown that rurioctocog alfa pegol prophylaxis successfully reduces ABR in adults and children with previously treated HA (NCT01599819 and NCT01736475 [PROLONG-ATE]; NCT02210091). 5,16 Realworld evidence suggests that initiating early prophylaxis may reduce the health care costs and long-term complications associated with bleeding events. 25 However, there is a paucity of research describing the patient experience and outcomes with EHL rFVIII outside of clinical trials. The current real-world study found that while receiving rurioctocog alfa pegol therapy, 39% of PWHA (n = 20/51) experienced no bleeding events. These data are somewhat lower than the real-world evidence previously reported by , which showed that 53% of PWHA (n = 8/15) experienced no bleeding events after switching to rurioctocog alfa pegol, 3 although the current study includes a more heterogeneous pediatric population. Taken together, this shows that data for PWHA treated with rurioctocog alfa pegol in routine clinical practice are consistent with data from the pivotal clinical studies.
In terms of factor consumption, the dose of EHL rFVIII is higher per infusion compared with SHL rFVIII. However, data from clinical trials indicate that overall consumption is similar for SHL and EHL rFVIII products. 20,21 Data from the current study found that PWHA who switched from an SHL rFVIII to rurioctocog alfa pegol reported lower mean dosing frequency and thus lower factor consumption with rurioctocog alfa pegol compared with their previous rFVIII. In the real-world study by Dunn et al., EHL rFVIII was shown to reduce factor consumption by 19% compared with SHL rFVIII therapy in patients with severe hemophilia A. 3 Coupled with the improved ABR observed with rurioctocog alfa pegol versus prior therapies in the current study, this suggests that the health outcome changes due to switching treatment should be taken into account when considering EHL rFVIII consumption.
PWHA who switched from an EHL rFVIII to rurioctocog alfa pegol (n = 4) also experienced a reduction in ABR, although this was not significant (P = 0.4). While this subgroup of PWHA was too small to allow meaningful comparisons to be drawn, there were trends toward clinical improvement with rurioctocog alfa pegol treatment versus prior EHL rFVIII. However, further work is needed to confirm this hypothesis.
In terms of treatment adherence, good-to-complete adherence to the rurioctocog alfa pegol prophylactic regimen was reported by 79% (n = 41/52) and 100% (n = 4/4) of all PWHA who switched from a prior SHL and EHL rFVIII, respectively. These rates are higher than the reported 53% of patients who adhered to both their prescribed frequency of administration for > 80% of study weeks and ≥ 80% of their prescribed FVIII doses in a separate non-interventional, prospective study of PWHA without inhibitors (n = 41 on SHL and n = 9 on EHL FVIII). Patient survey data show that the time-consuming nature of some prophylactic rFVIII regimens is the most prominent barrier to treatment adherence. 7,8,26 Data from the current study indicate that rurioctocog alfa pegol has a lower treatment burden versus SHL rFVIII. Lowering treatment burden by reducing the number of infusions and breakthrough bleeds were reported to be among the most common reasons for PWHA to switch to rurioctocog alfa pegol in the current study. These findings are supported by the study by Dunn et al., in which the most frequently reported reason for switching to rurioctocog alfa pegol was to reduce infusion frequency (14/15 PWHA). 3 However, it should be considered that the decision to switch treatments may also have been influenced by the treating physician.

Limitations
The limitations of this study are typical of retrospective observational studies in the real-world setting. PWHA were not randomized and observers were not blinded. The source data, which are from 3 specialty pharmacies, may not be representative of all PWHA in the United States. Also, as some subgroups (e.g., PWHA aged < 12 years, PWHA treated with a prior EHL rFVIII) were small in sample size, these results should be interpreted with caution. Bleeding rates were reported by patients, 3 PWHA did not report their bleeding rates on rurioctocog alfa pegol, and the effect of the physician-patient relationship in the decision to switch rFVIII therapies could not be assessed. Follow-up was for 6-12 months, as lengthier follow-up can be a challenge, although this duration of time is typical for treatment of hemophilia patients in randomized clinical trials. An assessment of therapy cost was not included in this analysis.

■■ Conclusions
These real-world data show that switching from an SHL rFVIII to rurioctocog alfa pegol reduced ABR, without increasing factor dosing frequency or consumption, while also positively influencing treatment adherence. Reducing the treatment burden associated with SHL rFVIII is the major factor driving PWHA to switch to rurioctocog alfa pegol. These real-world data are consistent with the results of the pivotal clinical trials where rurioctocog alfa pegol was shown to have a positive clinical effect on ABR. The results of this study highlight rurioctocog alfa pegol as an important additional option for the care of PWHA.