Indirect treatment comparisons of the gene therapy etranacogene dezaparvovec versus extended half-life factor IX therapies for severe or moderately severe haemophilia B.

INTRODUCTION: Etranacogene dezaparvovec gene therapy for haemophilia B demonstrated superior efficacy at 24 months in reducing bleeds versus a ≥6-month lead-in period of prophylaxis with FIX products in the phase 3 trial, HOPE-B. In the absence of head-to-head comparisons of etranacogene dezaparvovec versus FIX products, indirect treatment comparisons (ITC) can be used. AIM: To compare the efficacy of etranacogene dezaparvovec versus rIX-FP, rFIXFc and N9-GP using ITC, and support HOPE-B results. METHODS: Data were leveraged from Phase 3 pivotal trials: HOPE-B, PROLONG-9FP, B-LONG and Paradigm 2. Annualised bleeding rates (ABR), spontaneous (AsBR) and joint (AjBR) bleeding rates, percentage of patients with no bleeds, and FIX consumption were assessed using inverse probability of treatment weighting and matching adjusted indirect comparisons. RESULTS: Etranacogene dezaparvovec demonstrated statistically significantly lower bleeding rates versus all comparators. Rate ratios for ABR, AsBR and AjBR versus rIX-FP were 0.19 (p < .0001), 0.08 (p < .0001) and 0.09 (p < .0001), respectively. Rate ratios for ABR, AsBR and AjBR versus rFIXFc were 0.14 (p < .0001), 0.13 (p = .0083) and 0.15 (p = .0111), respectively. Rate ratios for ABR and AsBR, versus N9-GP were 0.24 (p = .0231) and 0.13 (p = .0071), respectively. Etranacogene dezaparvovec demonstrated significantly higher percentage of patients with no bleeds versus rIX-FP and rFIXFc; odds ratios: 17.60 (p < .0001) and 5.65 (p = .0037), respectively. Etranacogene dezaparvovec resulted in significantly lower FIX consumption than all comparators. CONCLUSIONS: ITC suggests that etranacogene dezaparvovec offers patients with haemophilia B (≤2% of normal FIX expression) a single dose treatment that can significantly reduce bleeding rates and eliminate routine infusions associated with FIX therapies.

Assessing prophylactic use and clinical outcomes in hemophilia A patients treated with rVIII-SingleChain and other common rFVIII products in Germany.

OBJECTIVE: To evaluate real-world outcomes with rVIII-SingleChain and other commonly used recombinant FVIII (rFVIII) products. METHODS: Hemophilia treatment centers in Germany (n = 21) contributed patient chart data. Inclusion criteria were prophylactic treatment with one of five rFVIII products for ≥8 weeks. RESULTS: Male patients (n = 225) were included: rVIII-SingleChain (n = 40), rFVIIIFc (n = 47), octocog alfa (rFVIII; n = 58), octocog alfa (BAY 81-8973; n = 40), or moroctocog alfa (n = 40). In patients with severe disease (n = 76), 66.6%, 70.0%, 20.0%, 7.7%, and 27.3% were dosed ≤2×/week, respectively. Irrespective of dosing frequency, mean annualized bleed rates (ABRs)/annualized spontaneous bleed rates (AsBRs) were 0.3/0.1, 0.8/0.4, 1.1/0.5, 1.5/0.8, and 1.4/0.6, and mean FVIII consumption (IU/kg/week) was 83.2, 97.2, 92.5, 104.0, and 102.1, respectively. Results for all patients were similar. Of the patients on prophylaxis with prior therapy and after switching to rVIII-SingleChain (n = 21), mean ABR/AsBRs were 0.7/0.3 and 0.2/0.0, respectively. After switching to rVIII-SingleChain, mean FVIII consumption reduced (109.4 vs 74.5 IU/kg/week), and percentage of patients dosed ≤2×/week increased (0% to 71.4%). CONCLUSIONS: rVIII-SingleChain prophylaxis provides excellent bleeding protection, with potentially lowest factor consumption among the products assessed. Patients who switched to rVIII-SingleChain prophylaxis reduced dosing frequency and consumption compared with prior treatment, with similar or potentially lower bleeding rates.

Impact of the change of copay policy in Medicare Part D on zoster vaccine uptake among Medicare beneficiaries in a managed care organization.

BACKGROUND: Kaiser Permanente Southern California (KPSC) adopted the Medicare Part D Tier-6 with zero patient copay for zoster vaccination in 2012. We assessed the impact of the implementation on zoster vaccination rate (GSK study identifier: HO-13-14,182). METHODS: Zoster vaccination rate was examined among an open cohort of ≥65-year-old Medicare Part D beneficiaries during 01/01/2008-06/30/2014, compared to ≥65-year-old commercial health plan members and 60-64-year-old members. The demographics, vaccination records, and insurance and benefit type were confirmed through KPSC electronic medical record databases. Person-time based vaccination rate was calculated for each observation interval (calendar month or year). The changes in annual rates in one year pre- (2011) and post- (2012) Tier-6 implementation were compared in a difference-in-difference analysis. Linear spline Poisson regression models were fitted to compare the secular trend of monthly rates during pre and post Tier-6 implementation (01/2012). RESULTS: Zoster vaccination rate increased in Medicare Part D beneficiaries after the implementation of zero copay. The increase in annual vaccination rate from 2011 to 2012 was marginally higher in Medicare Part D beneficiaries but not statistically significant (difference in rate ratio [RR] = 0.04, p > 0.05) compared to commercial health plan members. Among non-Hispanic white members, the difference of RR was 0.09 (p = 0.020) between Medicare Part D beneficiaries and ≥65-year-old commercial plan members, and it was 0.08 (p = 0.034) compared to 60-64-year-old commercial plan members. In secular trend analysis, we did not observe significant increase in overall and race stratified zoster vaccination rate attributable to the implementation of the Tier-6. CONCLUSIONS: The impact of Tier-6 on zoster vaccination was not substantial in elderly Medicare Part D beneficiaries in this population where a lower than average copay ($20 to $40) was applied prior to the Tier-6 implementation. Further research is necessary to explore the numerical relationship between vaccination and amount of copay. TRIAL REGISTRATION: GSK study identifier: HO-13-14,182.

A budget impact analysis comparing a Hydrofiber® ; dressing to an alginate dressing in managing exuding venous leg ulcers in France.

An Excel model was developed to compare total costs (including primary and secondary dressings only) of Hydrofiber(®) ; dressing (2010 branded price) versus an alginate dressing (generic or branded price) in managing exuding venous leg ulcers considering mean wear time and mean duration of exudate management phase, from the French Social Security perspective over 5 years (2011-2015). Budget impact (based on prevalence of venous leg ulcers in France) was estimated as the difference between scenario 1 (Hydrofiber(®) ; versus alginate dressing usage proportion increasing slightly per year) and Scenario2 (proportion remaining at 2010 levels). Annual costs and net savings per patient for the dressings were calculated in analyses 1 and 2. Analysis 1 (28-day mean exudate management phase for both Hydrofiber(®) ; and alginate dressing groups): total costs 66·82€ Hydrofiber(®) ;, 70·08€ generic alginate, 77·0€ branded alginate; net savings 3·26€ and 10·18€ for Hydrofiber(®) ; versus generic and branded alginate. Analysis 2 (mean exudate management phase of 22·2 versus 28 days for Hydrofiber(®) ; versus alginate): total costs 52·92€, 70·08€ and 77·0€, and net savings 17·10€ and 24·02€, accordingly. Total cost savings (budget impact scenario 1 minus scenario 2): Analysis 1 - 223 107€ and 696 304€ for Hydrofiber(®) ; versus generic and branded alginate dressings, respectively; Analysis 2 - 1 169 845€ and 1 643 042€ accordingly. Sensitivity analyses indicated that results are reliable. This conservative analysis shows that effective exudate management using Hydrofiber(®) ; dressing can produce sizeable cost savings.

Assessing health plan payer's budget impact of etranacogene dezaparvovec for the treatment of hemophilia B in the United States.

BACKGROUND: Etranacogene dezaparvovec is a recently approved gene therapy for people with hemophilia B (PwHB). Current standard of care is prophylaxis with factor IX (FIX) to prevent bleeding. Etranacogene dezaparvovec increases blood FIX levels such that FIX prophylaxis could be eliminated. OBJECTIVE: To estimate the budgetary impact of etranacogene dezaparvovec adoption and utilization in a commercial health plan of the United States. METHODS: A budget impact model was developed to evaluate the introduction of etranacogene dezaparvovec to treat severe or moderately severe hemophilia B. The model considered a hypothetical 1-million-member plan over a 5-year horizon. FIX therapy prophylaxis use was estimated based on a weighted average of relevant brands using US market share data. A scenario of etranacogene dezaparvovec adoption/utilization was compared with one without etranacogene dezaparvovec utilization. Two etranacogene dezaparvovec uptake (market share growth) analyses were performed: one with gradual uptake and alternatively assuming all eligible PwHB received etranacogene dezaparvovec in year 1. The one-time cost of etranacogene dezaparvovec was assumed to be $3.5 million. Other costs (FIX prophylaxis, disease monitoring, bleed management, and adverse events) were estimated from published literature. All costs were in 2022 US dollars. Bleed and adverse event rates were sourced from the HOPE-B trial comparing etranacogene dezaparvovec to previous FIX therapy prophylaxis. The model estimated annual and per-member per-month costs over 5 years. Secondary analyses were performed considering a 10-year horizon. RESULTS: In the 1-million-member health plan, an estimated 1.8 PwHB were eligible for treatment with etranacogene dezaparvovec. Gradual uptake of etranacogene dezaparvovec resulted in cumulative 5-year budget impact of $848,509 compared with a scenario without etranacogene dezaparvovec. In years 1-5, the incremental annual and per-member per-month costs ranged from $79,824 to $271,435 and from $0.007 to $0.023, respectively. In the alternative uptake analysis, etranacogene dezaparvovec became cost saving annually beginning in year 2 and cumulatively beginning in year 5, for a 5-year savings of $754,844. Secondary analyses over 10 years found both uptake analyses cost saving. Other scenarios considered did not affect results substantially. CONCLUSIONS: Introducing etranacogene dezaparvovec as treatment for PwHB would have a modest budget increase within 5 years after treatment but may become cost saving if all eligible PwHB were treated in year 1. Initiating PwHB on etranacogene dezaparvovec sooner may produce greater overall savings and earlier annual savings. Etranacogene dezaparvovec is a treatment option that may provide overall cost savings for US commercial health plans, which would increase as the plan size increases.

Analysis of long-term clinical and cost impact of etranacogene dezaparvovec for the treatment of hemophilia B population in the United States.

INTRODUCTION: Etranacogene dezaparvovec (EDZ), Hemgenix, is a gene therapy recently approved for people with hemophilia B (PwHB). OBJECTIVE: To estimate long-term clinical impact and cost of EDZ in the United States (US). METHODS: A decision-analytic model was developed to evaluate the long-term impact of introducing EDZ for PwHB over a 20-year time horizon. Factor IX (FIX) prophylaxis comparator was a weighted average of different FIX prophylaxis regimens based on US market share data. We compared a scenario in which EDZ is introduced in the US versus a scenario without EDZ. Clinical inputs (annualized FIX-treated bleed rate; adverse event rates) were obtained from HOPE-B phase 3 trial. EDZ durability input was sourced from an analysis predicting long-term FIX activity with EDZ. EDZ one-time price was assumed at $3.5 million. Other medical costs, including FIX prophylaxis, disease monitoring, bleed management, and adverse events were from literature. The model estimated annual and cumulative costs, treated bleeds, and joint procedures over 20 years from EDZ introduction. RESULTS: Approximately 596 PwHB were eligible for EDZ. EDZ uptake was estimated to avert 11,282 bleeds and 64 joint procedures over 20 years. Although adopting EDZ resulted in an annual excess cost over years 1-5 (mean: $53 million annually, total $265 million), annual cost savings were achieved beginning in year 6 (mean: $172 million annually; total $2.58 billion in years 6-20). The total cumulative 20-year cost savings was $2.32 billion, with cumulative cost savings beginning in year 8. CONCLUSION: Introducing EDZ to treat PwHB is expected to result in cost savings and patient benefit over 20 years. Initiating PwHB on EDZ sooner can produce greater and earlier savings and additional bleeds avoided. These results may be a conservative estimate of the full value of EDZ, as PwHB would continue to accrue savings beyond 20 years.

This analysis assessed the long-term clinical and financial impact of introducing EDZ in the United States of America for people with severe or moderately severe hemophilia B. A decision-analytic model was developed comparing a scenario with EDZ and one without EDZ over 20 years. Introducing EDZ would avert 11,292 bleeds and 64 joint procedures over 20 years and would achieve cumulative cost savings in year 8, with a total cumulative 20-year cost saving of $2.32 billion.

Matching-Adjusted Indirect Comparison of Recombinant Factor IX Albumin Fusion Protein Versus Recombinant Factor IX Fc Fusion Protein for Weekly Prophylactic Treatment of Hemophilia B.

INTRODUCTION: Prophylactic treatment of hemophilia B with recombinant factor IX (rFIX) molecules with enhanced pharmacokinetics including rIX-FP (albutrepenonacog alfa; Idelvion©) and rFIXFc (eftrenonacog alfa; Alprolix©) have commonly been used in the clinic. In the absence of head-to-head comparative trials, the aim of this study was to estimate the efficacy of rIX-FP versus rFIXFc using matching-adjusted indirect comparisons (MAICs). METHODS: MAIC analyses leveraged individual patient data from the PROLONG-9FP trial and published summary-level data from the B-LONG trial for subjects who received weekly prophylaxis regimens. Individual patient data were used to assign weights and balance subjects from PROLONG-9FP with subjects from B-LONG on baseline disease severity, age, prior FIX regimen, and body mass index (BMI). Six efficacy outcomes were analyzed including annualized bleeding rate (ABR), annualized spontaneous bleeding rate (AsBR), annualized joint bleeding rate (AjBR), and the proportion of subjects without bleeding events (for total, spontaneous, and joint bleeding events). RESULTS: After adjustment for baseline disease severity, age, prior FIX regimen, and BMI, rIX-FP was associated with a statistically significant decrease in AsBR (rate ratio [RR] 0.42; 95% confidence interval [CI] 0.22, 0.82; P = 0.0107), and the proportion of patients without bleeding events (odds ratio [OR] 3.24; 95% CI 1.41, 7.45; P = 0.0057), spontaneous bleeding events (OR 3.47; 95% CI 1.56, 7.73; P = 0.0023), and joint bleeding events (OR 2.41; 95% CI 1.10, 5.26; P = 0.0274) compared with rFIXFc. Prophylactic treatment with rIX-FP was also associated with a numerically lower ABR (RR 0.75; 95% CI 0.32, 1.75; P = 0.5095) and AjBR (RR 0.82; 95% CI 0.37, 1.82; P = 0.6178). CONCLUSION: The MAICs demonstrated that weekly prophylaxis treatment of severe hemophilia B with rIX-FP resulted in favorable efficacy outcomes as compared to rFIXFc. These findings suggest rIX-FP may offer improved clinical benefits over rFIXFc.

Assessing health care resource use, outcomes, and costs among Medicaid beneficiaries receiving factor IX prophylaxis for hemophilia B.

BACKGROUND: Hemophilia B is characterized by a deficiency of clotting factor IX (FIX), leading to excessive bleeding. Hemophilia B is commonly treated using replacement FIX therapy, which may be administered prophylactically or on-demand following a bleeding episode. Previous research has found high health care resource use (HCRU) and costs among Medicare and commercially insured people with hemophilia B (PwHB), with FIX therapy being a primary driver of health care costs. OBJECTIVE: To assess HCRU, outcomes, and costs among US Medicaid beneficiaries receiving FIX prophylaxis for hemophilia B. METHODS: This study employed a retrospective comparative cohort design to assess HCRU, outcomes, and costs among adult male Medicaid beneficiaries receiving FIX prophylaxis for hemophilia B, relative to a matched comparator population of beneficiaries without bleeding disorders. Nationwide Medicaid claims and enrollment data from 2015 to 2020 were used for this analysis. Adult male PwHB who received FIX prophylaxis, defined as not having identified gaps in FIX therapy exceeding 60-days during a 1-year measurement period, and were continuously enrolled in Medicaid for at least 2 years, were matched 1:4 to comparator beneficiaries without bleeding disorders based on baseline demographic and clinical characteristics. Key measures of HCRU and outcomes included inpatient hospital admissions, outpatient hematologist visits, and bleeding events. Measures of health care costs were assessed among a subset of beneficiaries enrolled in fee-for-service Medicaid. RESULTS: PwHB receiving FIX prophylaxis were significantly more likely to have multiple inpatient hospital admissions and had a longer cumulative length of stay per person relative to comparator beneficiaries (30.2 vs 14.8 days, respectively; P = 0.0473). PwHB receiving FIX prophylaxis also had significantly higher rates of bleeding events relative to comparator beneficiaries (0.54 vs 0.02 per person, respectively; P < 0.0001) and outpatient hematologist visits (1.58 vs 0.20 per person, respectively; P < 0.0001). Annual costs among PwHB receiving FIX prophylaxis were significantly higher than costs among comparator beneficiaries ($928,370 vs $34,553 per person, respectively; P < 0.0001) and were overwhelmingly driven by costs associated with FIX therapy. CONCLUSIONS: This analysis found higher rates of HCRU and costs among Medicaid beneficiaries receiving FIX prophylaxis for hemophilia B relative to a matched comparator population of beneficiaries without bleeding disorders. Future research should examine hemophilia B costs and outcomes within the context of new treatments with innovative mechanisms of action, such as gene therapies, RNA interference therapies, and antitissue factor pathway inhibitor therapies.

Economic and humanistic burden in kidney transplant rejection: a literature review.

INTRODUCTION: Antibody-mediated rejection (ABMR) is a major cause of late kidney allograft failure, but its economic and humanistic impacts have not been well-characterized in the literature. AREAS COVERED: We reviewed available literature on economic burden (costs and healthcare resource use) and humanistic burden (health-related quality of life impacts [HRQOL] and utility estimates) in patients diagnosed with kidney transplant rejection; ABMR-specific studies were of particular interest. In total, 21 publications reporting economic and humanistic burden were included in the review; 9 of these reported ABMR-specific outcomes. The reviewed studies consistently showed a greater burden associated with ABMR-related transplant rejection than with non-ABMR transplant rejection. EXPERT OPINION: Evidence suggests greater economic burden and increased HRQOL impairment with ABMR-related kidney transplant rejection relative to non-ABMR, although small sample sizes and missing definitions for ABMR make meaningful comparisons between studies challenging. Because no International Classification of Diseases (ICD)-10 codes currently describe the etiologies of transplant rejection, it is difficult to characterize the burden of distinct types of transplant rejection. The paucity of high-quality data on the burden of ABMR in kidney transplant rejection demonstrates the need for more etiology-centric ICD-10 codes.

Budget impact of prophylactic treatment of rVIII-SingleChain in moderate and severe hemophilia A in Italy.

INTRODUCTION: rVIII-SingleChain, a recombinant factor VIII (rFVIII), has demonstrated safety and efficacy in patients with hemophilia A in clinical trials and real-world evidence. This analysis aimed to estimate the potential budget impact of increasing the usage of rVIII-SingleChain for the prophylactic treatment of hemophilia A over 3 years in Italy. METHODS: Patients with moderate and severe hemophilia A receiving prophylaxis were included in the analysis. Epidemiological data were obtained from published literature. Mean product consumption and mean annual bleeding rate for rVIII-SingleChain, rFVIIIFc, octocog alfa and BAY 81-8973 were based on pooled real-world data from Italy, Germany and US. A budget impact model has been developed in order to compare two scenarios: a base-case scenario where current rVIII-SingleChain shares are kept constant over 3 years and an alternative scenario where rVIII-SingleChain shares increase by taking from other rFVIII products. Analysis 1 was based on the current Italian list prices and Analysis 2 considered current regional acquisition prices for both scenarios. RESULTS: Annually, adult patients treated with rVIII-SingleChain prophylaxis are expected to consume 324,589 units per patient, resulting in annual costs of €240,196 per patient. In Analysis 1, comparing the base case (constant market share of 9% rVIII-SingleChain over time) with the alternative scenario (higher rVIII-SingleChain market share and increasing from 15% in the first year to 25% in the third year), the total expenditure for prophylaxis using rFVIII products is expected to decrease by €1.4 million in Year 1, by €3.1 million in Year 2 and by €5.4 million in Year 3. In Analysis 2 based on regional prices, the results remained consistent. DISCUSSION/CONCLUSION: This analysis suggests that increasing utilization of rVIII-SingleChain in hemophilia A patients may lead to cost savings as a result of reduced consumption with uncompromised efficacy in bleed protection.

Why was the study done? Hemophilia A is a rare inherited bleeding disorder. People with severe hemophilia are more likely to bleed compared to people without hemophilia and bleeds can occur spontaneously or in response to trauma. Patients are treated with medication to reduce the chance of bleeding. However, the cost of treating patients with hemophilia can be high and place demands on the healthcare system.What did we do and find?This study looked at the cost of treating people with hemophilia in Italy and used a type of economic analysis (called budget impact modelling) to estimate the effect of increasing the use of a particular medication (rVIII-SingleChain), compared to other medications that are available. Different variations of the model were tested to compare a range of scenarios.The results of this analysis suggested that increasing the use of rVIII-SingleChain may lead to cost-savings for the Italian healthcare system, compared to using the other currently available treatments. This analysis suggests that the use of rVIII-SingleChain enables people with hemophilia A to remain protected from bleeds, whilst using less product compared to other available medications.What is the influence of this study on the wider field?This type of analysis can be useful to healthcare systems, to guide the decision-making process regarding which medications to use or when making decisions related to healthcare policy.

Analysis of pooled real-world data from Germany, Italy, and the United States of rVIII-SingleChain compared with standard- and long-acting FVIII products for prophylaxis of hemophilia A.

OBJECTIVE: To evaluate real-world annualized bleeding rates (ABRs), dosing frequency, and factor consumption of four recombinant FVIII (rFVIII) products using pooled data from centers in the US, Germany, and Italy. METHODS: De-identified patient medical chart data were collected from 48 hemophilia treatment centers in the US, Germany, and Italy. Patients included in this analysis had hemophilia A and were treated with rVIII-SingleChain, rFVIIIFc, octocog alfa, or BAY 81-8973 for ≥12 weeks. Where possible, patient selection considered age and disease severity in order to balance patient groups across products. Summary statistics were presented descriptively by product for dosing frequency, consumption, ABR/annualized spontaneous bleeding rate (AsBR), and corresponding percentage of patients with zero bleeds. Logistic regression was performed for patients with zero bleeds or zero spontaneous bleeds (vs. patients with any such bleeds). Generalized linear model regression was performed for ABR, AsBR, and consumption. All regression models included the product variable for comparison as well as additional independent variables for adjustment (age, weight, severity, and country for the consumption model, with the addition of consumption for the bleeding outcomes models). RESULTS: Overall, 616 patients were included (rVIII-SingleChain, n = 129; rFVIIIFc, n = 159; octocog alfa, n = 181; BAY 81-8973, n = 147). Dosing frequency was ≤2 times a week for 65.9%, 75.5%, 25.4%, and 40.1% of patients treated with rVIII-SingleChain, rFVIIIFc, octocog alfa, and BAY 81-8973, respectively. ABRs were not significantly different among products, with mean (median) values of 1.1 (0.0), 1.0 (0.0), 1.4 (1.0), and 1.9 (1.0) for rVIII-SingleChain, rFVIIIFc, octocog alfa, and BAY 81-8973, respectively. The percentage of patients with zero bleeds was comparable between rVIII-SingleChain and rFVIIIFc (59.7% vs. 62.3%; p =.916) and significantly higher for rVIII-SingleChain compared with octocog alfa (p <.001) and BAY 81-8973 (p =.003). Comparison of mean weekly consumption showed: rVIII-SingleChain (83.0 IU/kg/week) vs. rFVIIIFc (96.9; p =.055) and significantly lower for rVIII-SingleChain vs. octocog alfa (108.6; p <.001) and BAY 81-8973 (104.3; p =.001). The median values for weekly consumption were 85.7, 90.1, 100.1, and 98.5 IU/kg/week for rVIII-SingleChain, rFVIIIFc, octocog alfa, and BAY 91-8973, respectively. Similar trends were observed for all outcomes when analyzing the subgroups of patients aged ≥12 years and patients with severe disease (all age and ≥12 years). CONCLUSIONS: rVIII-SingleChain prophylaxis may provide improved bleed protection, less frequent dosing, and lower consumption compared with standard-acting FVIII products, and comparable protection and consumption to the other long-acting FVIII product, in patients with hemophilia A.

A Real-World Analysis of Commonly Prescribed FVIII Products Based on U.S. Medical Charts: Consumption and Bleeding Outcomes in Hemophilia A Patients.

BACKGROUND: Patients with hemophilia A are commonly treated with replacement recombinant factor VIII (rFVIII) products, which can be standard-acting or long-acting. Long-acting products have modifications, offering the potential for reduced dosing frequency while maintaining therapeutic benefit. Extended dosing intervals reduce patient burden and can improve quality of life and adherence. OBJECTIVE: To assess real-world data for the use of 6 commonly prescribed standard-acting and long-acting FVIII products in the United States: octocog alfa, BAY 14-2222, BAY 81-8973, rVIII-SingleChain, rFVIIIFc, and polyethylene glycol (PEG)-rFVIII. We summarized annualized bleeding rates (ABRs), dosing frequency, and factor consumption in patients treated with each product, with subgroup analyses for patients with severe disease. METHODS: De-identified patient data were collected from 11 hemophilia treatment centers in the United States. Patients treated with octocog alfa, BAY 14-2222, BAY 81-8973, rVIII-SingleChain, rFVIIIFc, or PEG-rFVIII prophylaxis for ≥ 8 weeks at the time of data collection were included in the analysis. Among the 6 treatment groups, matching was attempted for patient age and disease severity where possible. RESULTS: Data were obtained for 240 patients, of whom 191 patients had severe disease. Patients receiving long-acting FVIII products were dosed less frequently than those receiving standard-acting FVIII products. The proportion of patients dosed 2 times weekly or less was 65.0%, 70.0%, 72.5%, 25.0%, 40.0%, and 47.5% with rVIII-SingleChain, rFVIIIFc, PEG-rFVIII, octocog alfa, BAY 14-2222, and BAY 81-8973, respectively. Median ABRs ranged from 2.0 to 3.0 (mean 2.6 to 4.4) across the 6 products for all patients and were similar for patients with severe disease (median 2.0 to 3.0 and mean 2.5 to 4.8). The proportion of patients experiencing 0 bleeding episodes ranged from 7.5% to 25.0% for all patients and 12.0% to 28.6% for patients with severe disease. For all patients, median (mean) weekly FVIII product consumption was lowest for rVIII-SingleChain among the 6 products (P = 0.045); 91.9 (91.1) IU per kg per week for rVIII-SingleChain, 108.5 (103.6) for rFVIIIFc, 97.6 (111.0) for PEG-rFVIII, 114.0 (117.5) for octocog alfa, 102.5 (102.6) for BAY 14-2222, and 95.1 (100.7) for BAY 81-8973. Similar differences in weekly consumption among the 6 products were observed for patients with severe disease (P = 0.014). CONCLUSIONS: Real-world data demonstrate that long-acting products may be beneficial compared with standard-acting products because of reduced dosing frequency while maintaining effectiveness. The 6 products evaluated showed statistically comparable ABRs and percentage of patients with 0 bleeds for all patients including those with severe disease. rVIII-SingleChain demonstrated lowest mean consumption for all patients, as well as for patients with severe hemophilia A, which may lead to potential savings in health care costs. DISCLOSURES: This study was funded by CSL Behring. Simpson reports consulting honoraria for participation in advisory boards for Bayer, CSL Behring, HEMA Biologics, Novo Nordisk, Octapharma, and Takeda and speakers bureau for Bayer and Novo Nordisk. Yan and Desai are employees of CSL Behring. Maro is an employee of Adivo Associates, which conducted the analyses for this study. Data were presented in part at the Hemostasis and Thrombosis Research Society; May 9-11, 2019; New Orleans, LA; at the International Society on Thrombosis and Haemostasis; July 6-10, 2019; Melbourne, Australia; and have been published in part in "Comparing Factor Use and Bleed Rates in U.S. Hemophilia A Patients Receiving Prophylaxis with 3 Different Long-Acting Recombinant Factor VIII Products," by Mindy L. Simpson, Vidhi Desai, Géraldine S. Maro, Songkai Yan (J Manag Care Spec Pharm. 2020;26[4]:504-12).

The Authors Respond.

DISCLOSURES: No funding was received for the writing of this letter. Simpson reports consulting honoraria for participation in advisory boards for Bayer, CSL Behring, HEMA Biologics, Novo Nordisk, Octapharma and Takeda, and speakers bureau for Bayer and Novo Nordisk; Yan and Desai are employees of CSL Behring; Maro is an employee of Adivo Associates.

A systematic review evaluating the efficacy and factor consumption of long-acting recombinant factor VIII products for the prophylactic treatment of hemophilia A.

AIMS: Long-acting (LA) recombinant FVIII (rFVIII) products with extended dosing intervals have been developed for the treatment of hemophilia A; however, no direct head-to-head trial has been conducted to compare the efficacy of these products. MATERIALS AND METHODS: A systematic literature search was conducted to identify published Phase III clinical trials of prophylactic LA rFVIII treatment in previously treated patients aged ≥12 years, with moderate-to-severe hemophilia A (endogenous FVIII levels ≤2%). Studies that did not meet these criteria, or did not report the included outcomes, were excluded. Bleeding rates and consumption were extracted and summarized; only data for the dosing frequencies indicated in the US product labels (which are similar to those indicated in the European Medicines Agency labels) were included. RESULTS: Five articles met the inclusion criteria; these studies only included patients with severe hemophilia A. Treatment length, reported outcomes and dose (range: 20-65 IU/kg) varied between studies. Median annualized bleeding rate (ABR) (IQR) reported in the relevant studies was 1.14 (0.00-4.30), rVIII-SingleChain 2 or 3 times weekly; 1.6 (0.0-4.7), rFVIIIFc 2 times weekly followed by every 3-5 days; 1.9 (0.0-5.8), BAX855 2 times weekly; 1.18 (0.00-4.25), N8-GP every 4 days; 1.9 (0.0-5.2) and 4.1 (2.0-10.6), BAY 94-9027 2 times weekly for the cohort who experienced >1 or <1 bleed in the study run-in phase, respectively. Median spontaneous ABR was 0.0 across studies reporting relevant data. Reported consumption was comparable among all LA products. LIMITATIONS: The primary limitation of this systematic review was the variation in study design and not all studies reported all desired outcomes, which limited the quantity of data available. CONCLUSIONS: This systematic review identified pivotal trial data for LA rFVIII products. Real-world evidence is needed to understand how these products perform in clinical practice.

Comparing Factor Use and Bleed Rates in U.S. Hemophilia A Patients Receiving Prophylaxis with 3 Different Long-Acting Recombinant Factor VIII Products.

BACKGROUND: Recombinant factor VIII (rFVIII) products have been developed with improved pharmacokinetics, offering some patients the potential to extend dosing intervals, thereby reducing their dosing frequency while minimizing the occurrence of bleeding events. No clinical trials have been conducted to compare the bleeding rates and use of these long-acting products. OBJECTIVES: To (a) assess real-world use of prophylaxis regimens in patients using 1 of 3 different long-acting products-rVIII-SingleChain, rFVIIIFc, or PEG-rFVIII; and (b) compare bleeding rates, dosing frequency, and factor consumption in 3 cohorts of patients. For rVIII-SingleChain patients, these measures were also compared with the prior products these patients used. METHODS: De-identified patient chart data were collected from 11 hemophilia treatment centers in the United States. Patients were included if they had been treated with rVIII-SingleChain, rFVIIIFc, or PEG-rFVIII prophylaxis for ≥ 8 weeks at the time of data collection. Matching for age and disease severity was attempted between the 3 patient groups. Data were also collected for patients who switched from their prior FVIII product to prophylaxis with rVIII-SingleChain. RESULTS: Data were obtained for 120 male patients. The majority of patients were dosing 2 times per week or less frequently (rVIII-SingleChain 65.0%, rFVIIIFc 70.0%, and PEG-rFVIII 72.5%). Annualized bleeding rates were comparable among the 3 cohorts, with median (mean) values of 2.0 (2.6) with rVIII-SingleChain and rFVIIIFc, and 3.0 (3.7) with PEG-rFVIII. The overall median (mean) FVIII consumption in IU per kg per week (IU/kg/week) was 91.9 (91.1) with rVIII-SingleChain, 108.5 (103.6) with rFVIIIFc, and 97.6 (111.0) with PEG-rFVIII, resulting in expected mean annual consumption of 322,140 IU, 361,816 IU, and 373,100 IU, respectively, for a 70 kg patient aged ≥12 years. The mean consumption was significantly different among the 3 products for all patients (P = 0.0164) and for those dosed 2 times per week (P < 0.0001). Among patients infusing 2 times per week, median (mean) consumption with rVIII-SingleChain was 83.8 (81.2) IU/kg/week, compared with 109.6 (104.4) IU/kg/week for rFVIIIFc and 92.1 (91.5) IU/kg/week for PEG-rFVIII. Additionally, switching from prophylaxis with prior FVIII products to rVIII-SingleChain increased the proportion of patients dosing ≤ 2 times per week (20% to 65%), decreased mean consumption (103.3 to 91.9 IU/kg/week; P = 0.0164), and maintained the mean annualized bleeding rates (2.9 to 2.6; P = 0.5665). CONCLUSIONS: Results for rVIII-SingleChain confirm the findings from its pivotal trial. Analyses of annualized bleeding rates demonstrate comparable clinical outcomes of rVIII-SingleChain to the other 2 long-acting products assessed. In patients aged ≥ 12 years, rVIII-SingleChain prophylaxis may result in an 11.0% and 13.7% lower mean factor consumption than rFVIIIFc and PEG-rFVIII, respectively, representing a potential cost-saving opportunity of 34% in both cases-at the current wholesale acquisition cost of the corresponding products. In addition, in patients using rVIII-SingleChain prophylactically, consumption was reduced compared with their prior products, while bleeding control was well maintained. DISCLOSURES: This study was funded by CSL Behring. Analyses were conducted by Adivo Associates. Maro is an employee of Adivo Associates. Desai and Yan are employees of CSL Behring. Simpson has received consulting honoraria for participation in advisory boards for CSL Behring, Genentech, Octapharma, and Bioverativ and speakers bureau for Bayer and Novo Nordisk. Data were presented in part at the Hemostasis and Thrombosis Research Society; May 9-11, 2019; New Orleans, LA, and at the International Society on Thrombosis and Haemostasis; July 6-10, 2019; Melbourne, Australia.

Assessing bleeding rates, related clinical impact and factor utilization in German hemophilia B patients treated with extended half-life rIX-FP compared to prior drug therapy.

Objective: An extended half-life factor IX (FIX) fusion protein linking recombinant FIX with recombinant human albumin (rIX-FP), indicated for the treatment of hemophilia B, was approved by the European Medicines Agency in May 2016. We aimed to compare clinical outcomes and drug utilization in patients who switched from prior FIX therapies to rIX-FP.Methods: Anonymized patient chart data were collected from German institutions treating patients with hemophilia B. Patients were included if they had been treated with rIX-FP for ≥8 weeks at the time of data collection. Bleeding rates and FIX consumption were compared between rIX-FP and patients' prior FIX products.Results: Data were obtained for 81 male patients treated with rIX-FP, including 59 who received prophylaxis with both their prior drug and rIX-FP (prophylaxis-to-prophylaxis group). Mean factor consumption in this group was 44.2 IU/kg/wk for rIX-FP compared with 82.3 IU/kg/wk for all prior FIX products. In addition, intra-patient analysis of factor consumption showed lower consumption of rIX-FP compared with prior FIX in 56 of 59 patients. Among the patients for whom bleed data were available (n = 42), annualized bleeding rate decreased from a mean (standard deviation) of 2.6 ± 2.9 on prior product to 0.3 ± 0.6 on rIX-FP. The proportion of patients with zero bleeds increased from 24% with prior therapy to 81% with rIX-FP.Conclusion: rIX-FP was associated with substantial reductions in bleeding rates and consumption of FIX compared with standard half-life products that require more frequent administration.

Systematic review and analysis of efficacy of recombinant factor IX products for prophylactic treatment of hemophilia B in comparison with rIX-FP.

Aims: Prophylaxis with standard-acting recombinant factor IX (rFIX) in hemophilia B patients requires frequent injections. Extended half-life (EHL) products allow for prolonged dosing intervals, and so reduce this treatment burden. Three technologies are employed to extend the half-life of FIX; glycopegylation, Fc-fusion, and albumin fusion. rIX-FP is a novel albumin fusion protein, which allows for a prolonged dosing interval of up to 14 days. A systematic review and indirect statistical comparison was performed to evaluate the efficacy of both EHL and standard-acting rFIX products compared with rIX-FP in Phase III trials for prophylaxis in adult hemophilia B patients. Materials and methods: A systematic search was conducted in both EMBASE and PubMed to identify Phase III trials of prophylactic rFIX treatment in previously treated hemophilia B patients aged ≥12 years (FIX ≤2%). Annualized bleeding rate (ABR), spontaneous ABR (AsBR), and joint ABR (AjBR) data were extracted from each study. A z-test was performed using the mean of each parameter, and the mean difference in outcome between studies was calculated. Results: Seven articles investigating six rFIX products were identified. Median ABR, AsBR, and AjBR ranged from 0-3.0, 0-1.0, and 0-1.1 (means = 0.8-4.26, 0.13-2.6, and 0.34-2.85), respectively. rIX-FP achieved the lowest median and mean values in all three parameters. Z-tests showed that mean ABR was significantly lower for rIX-FP 7-day prophylaxis compared with the majority of standard-acting and other EHL rFIX products. Limitations: The low number of appropriate trials available for comparison limits the quantity of data available for comparison, and restricts the use of methods of adjustment for variance in study design or patient characteristics. However, these limitations are shared with similar analyses published in this field. Conclusion: This indirect comparison of Phase III trials indicates that rIX-FP efficacy compares favorably vs other rFIX products for prophylaxis in hemophilia B.

Analysis of Vascular Event Risk After Herpes Zoster From 2007 to 2014 US Insurance Claims Data.

OBJECTIVE: To estimate the risk of transient ischemic attack (TIA), stroke, and myocardial infarction in periods covering 4 weeks before to 52 weeks after herpes zoster (HZ) diagnosis in US adults. PATIENTS AND METHODS: This retrospective study (GSK study identifier: HO-15-15771) with matched cohorts used the Truven Health MarketScan Commercial and Medicare claims data set linked with obesity and smoking status information. Patients 18 years and older at the date of HZ diagnosis and 1-year pre- and post-HZ diagnosis continuous insurance enrollment (from January 1, 2007, through December 31, 2014) were propensity score matched to controls in terms of demographic characteristics, risk factors for vascular events, other comorbid disorders, general health, obesity, and smoking status. A post hoc sensitivity analysis was performed not matching for obesity and smoking status information. Adjusted incidence rate ratios (IRRs) were estimated using multivariate Poisson models during an aggregate period (1-month before and after the index date). RESULTS: A total of 23,339 patients with HZ were matched to 46,378 controls (mean age, 56 years; 45,173 [65%] women). During the aggregate period, patients with HZ were statistically significantly more likely to suffer a TIA: IRRs for all patients and patients aged 18 to 49 years were 1.56 (95% confidence interval [CI], 1.13-2.15) and 5.12 (95% CI, 1.37-19.10), respectively (P<.05); the respective IRRs for stroke were 1.40 (95% CI, 0.93-2.11) and 8.12 (95% CI, 0.93-71.27). In the sensitivity analysis, IRRs for TIA and stroke were statistically significantly increased regardless of age. CONCLUSION: Herpes zoster was associated with an increased risk of composite events, TIA, and stroke in adults in the period around diagnosis. More research on the HZ and vascular risk association is needed. GSK STUDY IDENTIFIER: HO-15-15771.

Is patient insurance type related to physician recommendation, administration and referral for adult vaccination? A survey of US physicians.

This study evaluated physician practices and perceived barriers for influenza, tetanus, diphtheria, pertussis (Tdap), and zoster vaccination of adults in the United States (US), with emphasis on patients with Medicare versus commercial insurance. A cross-sectional internet-based survey of board-certified general/family practitioners and internists (N = 1,000) recruited from a national US physician panel was conducted in May 2017. For influenza, rates of physician recommendation (84% of Medicare patients, 82% of commercially-insured patients), administration (80% Medicare, 78% commercial), and referral (11% Medicare, 11% commercial) were similar regardless of insurance type. Tdap recommendation was higher for commercial compared to Medicare patients (59% vs. 54%, p < 0.001); while zoster recommendation was higher for Medicare patients than commercial (59% vs. 55%, p < 0.001). For Tdap and zoster, higher administration rates were reported in commercial patients (64% Tdap, 36% zoster) than Medicare (56% Tdap, 32% zoster), and referral rates were higher for Medicare patients (19% Tdap, 49% zoster) than commercial (14% Tdap, 42% zoster). Over 40% of physicians would be much more likely to administer Tdap and zoster vaccines if they were covered under Medicare Part B, with more physicians indicating financial barriers as "major" or "moderate" for Medicare than commercial patients. These differences may be related to financial barriers associated with adult vaccinations that are covered under Medicare Part D and involve patient out-of-pocket costs. Efforts to reduce financial barriers associated with adult vaccinations covered under Medicare Part D and to improve patient and physician knowledge could positively impact physician recommendation, administration, and referral for adult vaccination in the US.

Costs of herpes zoster complications in older adults: A cohort study of US claims database.

BACKGROUND/OBJECTIVES: Herpes zoster (HZ) incidence increases with age, and the burden of HZ is expected to grow with aging of populations worldwide. We aim to determine the incremental healthcare resource utilization and associated costs of patients with common HZ-related complications other than postherpetic neuralgia (cutaneous, neurologic and ophthalmic) compared to uncomplicated HZ. METHODS: We conducted a retrospective cohort study of commercial health insurance claims covering about 40 million immunocompetent individuals aged ≥50 years at study entry from all over the US, from 2008 to 2013, with follow-up for one year after HZ onset. All-cause healthcare resource utilization and direct healthcare costs were recorded and calculated from six months before until 12 months after HZ onset. The mean costs for HZ patients with complications were compared to the mean costs for patients with uncomplicated HZ. Multivariable regression analyses estimated mean incremental costs adjusted for demographics, comorbidities, type of complication and time period. RESULTS: Over the five-year study period, 22,948 HZ patients (60% women, median age 62 years) who experienced at least one of the selected complications were compared to 213,232 patients (63% women, median age 61 years) with uncomplicated HZ. Overall, the mean annual incremental unadjusted costs for the patients with HZ-related complications were US$4716, ranging from US$2173 for ophthalmic to US$18,323 for neurologic complications. Most of the incremental costs associated with HZ complications were accrued during the first quarter after HZ onset. For each complication type the incremental costs increased with age up to, but not including the oldest group, aged ≥80 years. CONCLUSIONS: Approximately 10% of immunocompetent older patients with HZ develop complications which considerably increase the economic burden of HZ. Vaccination of older adults will offset some of the burden of HZ, including costs associated with HZ-related complications.