In the editorial entitled ‘Transition considerations for extended half-life factor products’, Drs Croteau and Neufeld emphasize the importance of balancing efficacy and cost-effectiveness in making treatment decisions, and suggest that the benefits of a reduced infusion frequency are not sufficient to warrant an increased cost per unit for extended half-life factor products 1. The authors make a number of assumptions about the transition to using extended half-life factors, but do not fully consider the key components of efficacy, cost, treatment burden, and ease of adherence that undoubtedly impact the decision-making of patients, caregivers, and health-care providers. The authors note that an ideal prophylaxis regimen ‘simultaneously minimizes both bleeding events and excessive factor usage’, and suggest that reduction in the frequency of infusions should not be achieved at the expense of either. Clinical data for the extended half-life factor products recombinant factor VIII Fc fusion protein (rFVIIIFc) and recombinant factor IX Fc fusion protein (rFIXFc) support this goal. The clinical value of rFVIIIFc and rFIXFc for both the prevention and treatment of bleeding in previously treated patients with severe haemophilia A and B, respectively, has been demonstrated in multicentre, international clinical studies in children, adolescents and adults (Table 1) 2-5. In the A-LONG study, annualized bleeding rates were low with rFVIIIFc prophylaxis administered 1–2 times per week, and most acute bleeding episodes were controlled with a single infusion 2. The low bleeding rates observed in A-LONG are further supported by data from the rFVIIIFc extension study, ASPIRE, during which participants from A-LONG who received individualized prophylaxis with rFVIIIFc had an annualized bleeding rate of 0.66 (median follow-up: 81 weeks) 4. Similarly, in the B-LONG study annualized bleeding rates were low with rFIXFc prophylaxis administered approximately every 1–2 weeks, with most acute bleeds controlled with a single infusion 3. Cost-effectiveness analyses are used by health-care decision-makers to weigh the cost of treatment against the outcome achieved. Proper analytical design is crucial in the development of cost-effectiveness models, and should include considerations for treatment price per unit, consumption, and direct and indirect costs. The ISPOR Drug Cost Task Force recommends that cost-effectiveness analyses use net drug prices that more accurately reflect true societal drug costs, including various discounts or rebates provided by manufacturers or other adjustments (average discount: 20%–60% of gross list price) 6. Thus, it is inaccurate for the authors to compare annual costs of treatment using net discounted prices for standard half-life factors and publically available gross list prices for rFVIIIFc and rFIXFc. Additionally, to achieve a true comparison, drug costs used in cost-effectiveness analyses must also reflect different dosing regimens and use patterns in the real world, rather than simply relying on the respective product package inserts 6. In their evaluation of considerations for transitioning to extended half-life products, the authors compared the typical dosing regimens for standard half-life products in their own single practice in the United States (U.S.) with the regimens for rFVIIIFc and rFIXFc outlined in the respective U.S. FDA-approved package inserts (i.e. product labels) 1. It should be noted that the authors’ dosing regimens are not necessarily reflective of the practices in other U.S. clinics, and may not be applicable to those in other regions of the world. In general, clinicians have had 10+ years of experience with standard half-life factors and are familiar with strategies for optimizing the dosing of these products. As the first available extended half-life factor products, rFVIIIFc and rFIXFc have only recently come to market, and real-world experience with their dosing is evolving. The dosing regimens in the U.S. package inserts provide a recommended starting dose that can be further adjusted according to individual patient needs. Clinical trial data suggest that the initial conversion to treatment with rFVIIIFc and rFIXFc can be done empirically, without the need for pharmacokinetic evaluations 7, 8. As more clinical experience is gained with extended half-life factor products, the actual dosing and resulting utilization will be individualized within the framework of the label to meet the needs of patients, just as it occurs with standard half-life factor products. This aspect should be considered when evaluating the true cost-benefit of extended half-life factor products in the real world. Our best understanding of utilization is derived from retrospective analyses conducted using a database composed of aggregate U.S. Specialty Pharmacy Provider records for standard half-life FVIII and FIX replacement therapies. These analyses indicate that median real-world consumption in the U.S. is 98.4 IU kg−1 week−1 for rFVIII products (n = 520 patients) and 134.7 IU kg−1week−1 for rFIX products (n = 118 patients) 9. While rFVIIIFc and rFIXFc have recently been approved and real-world data are still emerging, a subgroup analysis of U.S. participants from the individualized prophylaxis arm of A-LONG demonstrated reduced weekly prophylactic factor consumption (median weekly prophylactic dose for prestudy FVIII was 99.0 IU kg−1 week−1 vs. 80.2 IU kg−1 week−1 for rFVIIIFc), coupled with reductions in infusion frequency and lower bleeding rates with rFVIIIFc compared with their prestudy FVIII prophylaxis routines 10. Similarly, U.S. participants in the B-LONG study who received weekly rFIXFc prophylaxis also experienced reduced factor consumption (median weekly prophylactic dose for prestudy FIX was 165.0 IU kg−1 week−1 vs. 47.3 IU kg−1 week−1 for rFIXFc) with reduced infusion frequency and low bleeding rates 11. The U.S. retrospective and prestudy clinical trial prophylactic consumption data for standard half-life factors, coupled with U.S. clinical trial prophylactic consumption data for rFVIIIFc and rFIXFc, suggest that patients who transition to therapy with Fc factor products can expect to achieve low bleeding rates while experiencing a reduction in infusion frequency and utilizing lower amounts of factor than patients receiving standard half-life factor products. Lastly, the cost of treatment should be weighed against the outcome achieved (e.g. cost per bleeding episodes avoided). Depending on the point of view (patient, payer or societal views), cost-effectiveness analyses should incorporate patient and caregiver perspectives related to both direct costs (clinician visits, laboratory testing, outpatient procedures, hospitalization/emergency room visits) and indirect costs (productivity losses for patients and their caregivers, unpaid time costs for caregivers), a patient's ability to adhere to a treatment regimen, and quality of life. The real-world consumption data cited above suggest extended half-life factors have the potential for decreased factor utilization with less frequent administration, which offers the possibility of improved acceptance of prophylaxis and may ultimately result in improved patient health outcomes. Consideration of these assumptions and perspectives will certainly impact decision-making for patients, clinicians and payers. Extended half-life Fc fusion factors provide the opportunity for optimized prophylaxis regimens with less frequent infusions, and have the potential to bring patients closer to the treatment goals of continuous prophylaxis. Clinical trial data for rFVIIIFc and rFIXFc indicate that extension of dosing intervals is possible while maintaining low bleeding rates, with comparable or reduced factor consumption. As physicians become more experienced with dosing extended half-life factors, real-world usage data will add to the body of evidence informing the value of these products, and will help to enable appropriate patient-centred decisions regarding treatment. Biogen is committed to understanding the real-world consumption and outcomes of these products in order to increase opportunities for tailoring prophylactic treatment to achieve optimal patient outcomes. Editorial support was provided by MaryEllen Carlile Klusacek, PhD, an employee of Biogen. All authors contributed to the development of this letter, critically reviewed all drafts, and approved the final version. All authors are employees and shareholders of Biogen.
OBJECTIVE: To conduct a retrospective longitudinal analysis of natalizumab initiators to test the association of changes in natalizumab treatment patterns with differences in mean annual relapses and relapse-related costs. BACKGROUND: Natalizumab disease-modifying therapy for relapsing-remitting multiple sclerosis (MS) is efficacious in randomized controlled trials. Little is known about real-world treatment patterns and their impact on relapses and relapse-related costs. DESIGN/METHODS: Using the IMS PharMetrics Plus claims database (years 2006-2012), we identified MS patients who initiated natalizumab (no natalizumab claims in year prior) and had at least two years of follow-up. Persistence in annual follow-up periods was defined as no 90 day or greater gap in natalizumab claims. Relapse was an MS-related hospitalization or MS-related emergency or outpatient visit with intravenous or oral steroid burst claim within 7 days. Analyses compared observations for natalizumab treatment patterns from one year to the next (e.g. persistent to non-persistent), estimating differences in mean annual relapses and mean annual relapse-related costs. RESULTS: A total of N=2,407 natalizumab initiators had at least two years of follow-up, yielding 4,770 year-to-year natalizumab treatment patterns where each patient contributed one, two, or three year-to-year treatment patterns. 3,187 treatment patterns were persistent in the year prior; 731 (22.9%) of these transitioned to non-persistence. The remaining 1,583 treatment patterns were non-persistent in the year prior; 132 (8.3%) of these transitioned to persistence. Persistent to non-persistent treatment patterns had annual mean increase in relapses (0.23; 95% CI: 0.12, 0.34), and relapse-related costs ($1,324; 95% CI: $300, $2,347). Non-persistent to persistent had annual mean decrease in relapses (0.15; 95% CI: -0.32, 0.01), and relapse-related costs ($1,006; 95% CI: -$2,111, $200). CONCLUSIONS: Findings suggest that real-world persistent natalizumab users who become non-persistent have meaningful and statistically significant increases in annual relapses and relapse-related costs. Those who transition from non-persistent to persistent have trends toward reductions in relapses and their costs. Study Supported by: Biogen Idec
Abstract Background The melanocortin-4 receptor (MC4R) pathway is a key regulator of energy balance. Heterozygous variants of the genes for proopiomelanocortin (POMC), leptin receptor (LEPR), and proprotein convertase subtilisin/kexin type 1 (PCSK1) upstream of MC4R can result in impaired signaling in the MC4R pathway. This impaired signaling can lead to hyperphagia and early-onset, severe obesity. Setmelanotide (SET), an MC4R agonist, reduced weight and hunger after 3 months in patients with obesity due to these heterozygous variants in an earlier Phase 2 study. The current analysis is the first to assess continued efficacy of an additional year of SET treatment in patients with obesity due to heterozygous affectation of POMC, PCSK1, and LEPR. Methods Patients aged ≥6 years with obesity due to heterozygous variants in POMC, PCSK1, and LEPR were eligible for this long-term extension (LTE) trial (NCT03651765) after completing an index trial in which they received SET and demonstrated clinical benefit and acceptable safety as determined by the investigator. Patients received a minimum of 4 months of SET treatment in the index trial and began the LTE immediately following the completion of the index trial. Study visits occurred every 3 months and evaluated changes in body weight measures and assessed safety and tolerability. The current analysis reports outcomes after 1 year total of SET treatment across the index and LTE trials, relative to index trial baseline. Results As of October 29, 2021, 35 patients with obesity heterozygous for POMC, PCSK1, and LEPR had enrolled in the index trial, with 16, 17, and 17 patients continuing into the LTE trial and receiving at least 6, 9, and 12 months of treatment with SET, respectively. At index trial baseline, mean (standard deviation [SD]) body mass index (BMI) for all index trial patients was 50.26 (9.41) kg/m2, body weight in patients ≥18 years old was 142.97 (28.70) kg, and BMI Z score in patients <18 years old was 4.04 (0.65). Mean (SD) percent change in BMI was −6.93% (9.13%; n=16), −8.14% (10.13%; n=17), and −7.83% (9.69%; n=17) after 6, 9, and 12 months of treatment, respectively. Of 15 patients ≥18 years old, the mean (SD) percent change in body weight was −10.24% (7.90%; n=15) after 12 months. For the 1 patient <18 years old, mean change in BMI Z score was 0.64 after 12 months. No new safety concerns emerged during the LTE and 1 patient discontinued due to an adverse event, likely unrelated to treatment. Conclusions Treatment with SET had continued efficacy in patients with obesity due to heterozygous variants in POMC, PCSK1, and LEPR after 1 year of treatment. These data support the continued investigation of SET in these patients, which is underway in the Phase 3 EMANATE trial (NCT05093634). Presentation: Sunday, June 12, 2022 11:00 a.m. - 11:15 a.m.
Central venous access devices (CVADs) facilitate repeated or urgent treatments for paediatric haemophilia patients, but are associated with complications. This study examined the burden of illness, healthcare utilization and costs for CVADs in a real-world hospital setting.This study included haemophilia patients ages ≤18 years with discharges during 2006-2014 in the US Premier Healthcare Database. Haemophilia was identified using ICD-9 diagnosis codes and CVAD exposure using billing information. After matching haemophilia patients with and without CVADs on demographic and clinical characteristics, we compared infection, thrombosis, length of stay (LOS), inflation-adjusted hospital cost (2014 $USD) and readmission outcomes using generalized estimating equation models adjusted for hospital teaching status.Among 4793 paediatric haemophilia patients treated at one of 548 hospitals, a total of 197 patients were identified with CVAD exposure. The matched sample included 310 haemophilia patients (155 CVAD and 155 non-CVAD). CVAD cases had greater frequencies of all-cause infections (29% vs 17%, P = .01) and thrombosis (6% vs 1%, P = .06), longer adjusted mean LOS (9.5 vs 4.7 days, P = .002), higher adjusted mean inpatient total hospitalization costs ($47200 vs $25389, P = .02) as well as more inpatient and outpatient visits at 30-, 60- and 90-days (P < .05 for all differences) compared with non-CVAD patients.Paediatric haemophilia patients with CVADs experienced greater infection rates, healthcare utilization and higher hospitalization costs compared with non-CVAD patients. The results of this study may inform further research efforts to understand the costs and benefits of novel treatment alternatives for young haemophilia patients requiring CVADs.
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