Cost-effectiveness of prophylaxis with recombinant vs plasma-derived VWF in severe von Willebrand disease in the United States.

ABSTRACT: We evaluated the cost-effectiveness of prophylaxis with recombinant von Willebrand factor (rVWF) vs with plasma-derived von Willebrand factor (pdVWF) for patients with severe Von Willebrand disease. We found that rVWF is a cost-saving factor replacement compared with pdVWF across all willingness-to-pay thresholds in the United States.

[Haemophilia B therapy: impact of the reimbursability of a long-acting recombinant factor on pharmaceutical expenditure in Italy]. / Terapia dell'emofilia B: impatto dell'ammissione alla rimborsabilità di un fattore ricombinante long-acting sulla spesa farmaceutica in Italia.

OBJECTIVES: to assess the variability in expenditure compared to 2022 assuming different rates of shifting of therapy days from current active ingredients used for the treatment of haemophilia B to nonacog beta pegolDesign: descriptive cross-sectional study. SETTING AND PARTICIPANTS: consumption in the year 2022 (data source: Medicines Utilisation Monitoring Centre, Italian Medicines Agency) of all medicinal products available in Italy containing coagulation factor IX. MAIN OUTCOMES MEASURES: for each active ingredient, the total number of therapy days and the variability in expenditure compared to 2022 were estimated on the basis of a switch of therapy days, between 5% and 20%, to nonacog beta pegol. RESULTS: on the basis of considered scenarios, the analysis shows that the total annual expenditure for clotting factors used in the treatment of haemophilia B could remain at most unchanged or reduced. Particularly, the extent of the reduction in spending could vary from 0.11% to 2.26%. This trend would be in contrast to the stable increase seen in recent years, particularly in 2022. CONCLUSIONS: this predictive spending assessment may be useful in evaluating the economic impact from new treatment options, such as etranacogene dezaparvovec gene therapy already approved by the European Medicines Agency and the Food and Drug Administration, and to improve pharmaceutical governance.

A comparative assessment of neutropenia events, healthcare resource use, and costs among cancer patients treated with lipegfilgrastim compared with pegfilgrastim in Germany.

PURPOSE: We assessed the occurrence of neutropenia and febrile neutropenia (FN) and the associated healthcare resource in cancer patients receiving myelosuppressive chemotherapy in combination with pegfilgrastim versus lipegfilgrastim. METHODS: This is a retrospective analysis using a German health insurance claims database. Adults receiving chemotherapy with a prescription code for pegfilgrastim (n = 734) or lipegfilgrastim (n = 346) were observed over a 1-year follow-up period. Patient subgroups were analyzed according to cancer type and FN risk. FN risk was based on the chemotherapy regimen and any additional neutropenia risk factors. Outcomes were adjusted via regression analysis. RESULTS: Most patients were classified as high FN risk (70.0% pegfilgrastim; 65.6% lipegfilgrastim cohort). The mean age was 58.2 years in the pegfilgrastim cohort and 58.0 years in the lipegfilgrastim cohort, with more female patients than male patients (77.3% vs 79.8%, respectively), and the majority had breast cancer (64.9% and 68.8%, respectively). Overall, 10.0% and 10.4% of patients receiving pegfilgrastim or lipegfilgrastim experienced a neutropenia event (p = 0.82), with 4.4% and 3.5% of patients experiencing a FN event (p = 0.49). The mean neutropenia event-related healthcare costs were €604 and €441 for the pegfilgrastim and lipegfilgrastim cohorts; among patients with lymphoma, these costs were significantly greater (p = 0.03) with pegfilgrastim (€1,612) versus lipegfilgrastim (€382). The mean all-cause hospitalizations were significantly (p < 0.01) higher for lymphoma patients receiving pegfilgrastim (2.76) versus lipegfilgrastim (1.60). CONCLUSION: Overall, patients treated with pegfilgrastim and lipegfilgrastim were comparable in terms of neutropenia occurrences in the 1-year follow-up. In patients with lymphoma, neutropenia event-related healthcare costs and all-cause hospitalizations were significantly higher with pegfilgrastim compared with lipegfilgrastim in this study; however, this should be interpreted with caution in light of the limited sample size and the absence of clinical information.

Economic Evaluation of Andexanet Versus Prothrombin Complex Concentrate for Reversal of Factor Xa-Associated Intracranial Hemorrhage.

[Figure: see text].

Assessing the cost and quality-of-life impact of on-demand-only medications for adults with hereditary angioedema.

Background: Novel subcutaneous (SC) prophylactic therapies are transforming the treatment landscape of hereditary angioedema (HAE). Although questions are being raised about their cost, little attention has been paid to the cost and quality of life (QoL) impact of using on-demand-only medications. Objective: We assessed the overall economic burden of on-demand-only treatment for HAE and compared patient QoL with patients who received novel SC prophylactic therapies. Methods: US Hereditary Angioedema Association members were invited to complete an anonymous online survey to profile attack frequency, treatment use, and the presence of comorbidities as well as economic and socioeconomic variables. We modeled on-demand treatment costs by using net pricing of medications in 2018, indirect patient and caregiver costs, and attack-related direct billed costs for emergency department admissions, physician office visits, and/or hospitalizations. QoL was assessed by using the Angioedema Quality of Life questionnaire. Results: A total of 1225 patients (31.4%) responded. Of these, 737 adults with HAE (type I or II) met the inclusion criteria and completed the survey. Per patient/year direct costs associated with modeled on-demand-only treatment totaled $363,795, with additional indirect socioeconomic costs of $52,576 per patient/year. The greatest improvement in QoL was seen in patients who used novel SC prophylactic therapies, with a 59.5% (p < 0.01) improvement in median impairment scores versus on-demand-only treatment. In addition, patients who used novel SC prophylactic therapies reported a 77% reduction in the number of attacks each year when compared with those who used on-demand-only treatment. Conclusion: Our real-world patient data showed the cost and QoL burden of HAE treatment with on-demand-only therapy. Use of novel SC prophylaxis can lead to sizeable reductions in attack frequency and statistically significant and clinically relevant improvements in QoL. These data could be useful to clinicians and patients as they consider therapy options for patients with HAE.

Request for an Andexxa Value Analysis.

This perspective is a formal request to the American College of Cardiology and American Heart Association (ACC/AHA) to perform a value analysis on andexanet (Andexxa) similar to what was completed for the PCSK9 inhibitors in the 2018 ACC/AHA Blood Cholesterol guidelines. Based on the safety and efficacy concerns of andexanet alfa, a value statement in and or as an addendum to society guidelines is vital considering the high cost of therapy. In this era of ever-increasing health care costs, every clinician, health system, national society, insurer, and pharmaceutical company should work to be good stewards of our society's resources.

Cost comparison of andexanet versus prothrombin complex concentrates for direct factor Xa inhibitor reversal after hemorrhage.

Andexanet-alpha is a specific reversal agent for direct factor Xa inhibitors (dFXaI). We aimed to project utilization rates and cost of andexanet for reversal of dFXaI-related major hemorrhage compared to 4-factor prothrombin complex concentrates (4F-PCC). A retrospective, multicenter review was conducted between 1/1/2014 and 7/15/2018 of patients who received 4F-PCC for reversal of dFXaI-related life-threatening hemorrhages. Total hospital reimbursements/patient were calculated based on national average MS-DRG payments adjusting for Medicare discounts. The projected cost for andexanet (based on dose and insurance) and % reimbursement/patient was compared to the actual cost of 4F-PCC. Hemostasis at 24 h (excellent/good vs. poor) and 30-day thrombotic complications were assessed. Of 126 patients who received 4F-PCC to reverse dFXaI, 46 (~ 10 per-year) met inclusion criteria. The median projected cost of andexanet was $22,120/patient, compared to $5670/patient for 4F-PCC (P < 0.001). The median hospital reimbursement was $11,492/hospitalization. The projected cost of andexanet alone would exceed the entire hospital reimbursement in 74% of patients by a median of $7604, while 4F-PCC cost exceeded the total hospital payments in 7% of patients in the same cohort (P < 0.001). Hemostasis was excellent/good in 72% of patients post-4F-PCC, compared to 82% in andexanet trials. Thromboembolic events occurred in 4% of patients following 4F-PCC versus 10% in andexanet trials. The projected cost of andexanet would exceed the national average hospital reimbursement/patient in nearly 75% of patients by over $7500/hospitalization. 4F-PCC was significantly less expensive, had lower rates of thrombosis, but also lower rates of good/excellent hemostasis compared to published data for andexanet.

Emergent reversal of oral factor Xa inhibitors with four-factor prothrombin complex concentrate.

BACKGROUND: Controversy exists regarding first-line use of the recently approved reversal agent andexanet alfa due to limitations of the ANEXXA-4 study, thrombotic risks, and high medication acquisition cost. The purpose of this study was to evaluate the safety and effectiveness of 4F-PCC for the reversal of emergent oral fXa inhibitor-related bleeding. Furthermore, we aimed to evaluate a subgroup using strict ANNEXA-4 patient selection criteria. METHODS: This was a retrospective study conducted utilizing chart review of adult patients that received 4F-PCC for oral fXa inhibitor-related bleeding. The primary endpoint was the rate of clinical success defined as achieving excellent or good hemostatic effectiveness following the administration of 4F-PCC. Secondary endpoints included in-hospital mortality and arterial/venous thromboembolism, and cost compared with andexanet alfa. RESULTS: A total of 119 patients were included, with 83 patients in the ANNEXA-4 criteria subgroup. Eighty-five of the 119 patients (71%) required reversal due to intracranial bleeding. Prior to reversal, 70 patients (59%) were taking apixaban and 49 patients (41%) were taking rivaroxaban. Clinical success was achieved in 106 of 119 patients (89%) and 74 of 83 patients (90%) in the strict criteria subgroup. Three of 119 patients (2.5%) had a thrombotic event during hospital stay and the overall mortality rate was 13%. The average cost increase of andexanet alfa compared to 4F-PCC would have been $29,500 per patient. CONCLUSIONS: Administration of 4F-PCC for the reversal of oral fXa inhibitors was effective with relatively low thrombotic risk. Further direct prospective comparison of 4F-PCC to andexanet alfa is warranted.

[Cost-effectiveness of primary prophylaxis with PEG-rhG-CSF in early-stage breast cancer patients receiving chemotherapy in China].

Objective: To evaluate the cost effectiveness of primary prophylaxis (PP) with pegylated recombinant human granulocyte colony stimulating factor (PEG-rhG-CSF), PP with recombinant human granulocyte colony stimulating factor (rhG-CSF) and no prophylaxis in women with early-stage breast cancer in China. Methods: Two phase Markov models were constructed for a hypothetical cohort of patients aged 45 with stage Ⅱ breast cancer. The first phase modelled costs and outcomes of 4 cycles docetaxel combined with cyclophosphamide [TC×4, febrile neutropenia (FN) risk>20%] chemotherapy, which assumptions based on literature reviews, including FN rates [base-case (deterministic sensitivity analysis range), 0.29 (0.24-0.35)] and related events [FN case-fatality, 3.4 (2.7-4.1)]. Second phase modelled the long term survival which was link with the relative dose intensity (RDI) [mortality hazard ratio (HR) of RDI < 85% vs ≥85%, 1.45 (1.00-2.32)]. Clinical effectiveness, therapeutic costs, and economic utilities were estimated from peer-reviewed publications and expert opinions in case of unavailability of published evidences. Results: Compared to rhG-CSF PP and no prophylaxis, the cost of PEG-rhG-CSF PP increased to 5 208.19 RMB and 5 222.73 RMB, respectively. The quality-adjusted life-years (QALYs) enhanced to 0.066 and 0.297, respectively. Accordingly, the incremental cost effectiveness ratios (ICERs) are 79 146.3 RMB and 17 558.77 RMB per QALY, which were both below the willingness to pay (WTP) threshold of three times GDP per capita (18, 000 RMB) recommended by the WHO. Sensitivity analysis suggested that the more clinically effective the primary prophylaxis with PEG-rhG-CSF is, the more cost-effective primary prophylaxis with PEG-rhG-CSF will be. And the lower the mortality HR of RDI<85% vs ≥85% is, the more cost-effective primary prophylaxis with PEG-rhG-CSF will be. Conclusion: Although the cost of PP PEG-rhG-CSF is higher, considering the additional benefits, the administrating of PP PEG-rhG-CSF is likely to be a cost-effective alternative to PP rhG-CSF and no prophylaxis in patients with early stage breast cancer whose FN risks are more than 20% in China.

Cost-effectiveness of intrapleural use of tissue plasminogen activator and DNase in pleural infection: evidence from the MIST2 randomised controlled trial.

The MIST2 (Second Multicentre Intrapleural Sepsis Trial) trial showed that combined intrapleural use of tissue plasminogen activator (t-PA) and recombinant human DNase was effective when compared with single agents or placebo. However, the treatment costs are significant and overall cost-effectiveness of combined therapy remains unclear.An economic evaluation of the MIST2 trial was performed to assess the cost-effectiveness of combined therapy. Costs included were those related to study medications, initial hospital stay and subsequent hospitalisations. Outcomes were measured in terms of life-years gained. All costs were reported in euro and in 2016 prices.Mean annual costs were lowest in the t-PA-DNase group (EUR 10 605 for t-PA, EUR 17 856 for DNase, EUR 13 483 for placebo and EUR 7248 for t-PA-DNase; p=0.209). Mean 1-year life expectancy was 0.988 for t-PA, 0.923 for DNase, and 0.969 for both placebo and t-PA-DNase (p=0.296). Both DNase and placebo were less effective, in terms of life-years gained, and more costly than t-PA. When placebo was compared with t-PA-DNase, the incremental cost per life-year gained of placebo was EUR 1.6 billion, with a probability of 0.85 of t-PA-DNase being cost-effective.This study demonstrates that combined t-PA-DNase is likely to be highly cost-effective. In light of this evidence, a definitive trial designed to facilitate a thorough economic evaluation is warranted to provide further evidence on the cost-effectiveness of this promising combined intervention.

Cost-effective production of tag-less recombinant protein in Nicotiana benthamiana.

Plants have recently received a great deal of attention as a means of producing recombinant proteins. Despite this, a limited number of recombinant proteins are currently on the market and, if plants are to be more widely used, a cost-effective and efficient purification method is urgently needed. Although affinity tags are convenient tools for protein purification, the presence of a tag on the recombinant protein is undesirable for many applications. A cost-effective method of purification using an affinity tag and the removal of the tag after purification has been developed. The family 3 cellulose-binding domain (CBM3), which binds to microcrystalline cellulose, served as the affinity tag and the small ubiquitin-related modifier (SUMO) and SUMO-specific protease were used to remove it. This method, together with size-exclusion chromatography, enabled purification of human interleukin-6 (hIL6) with a yield of 18.49 mg/kg fresh weight from leaf extracts of Nicotiana benthamiana following Agrobacterium-mediated transient expression. Plant-produced hIL6 (P-hIL6) contained less than 0.2 EU/µg (0.02 ng/mL) endotoxin. P-hIL6 activated the Janus kinase-signal transducer and activator of transcriptional pathways in human LNCaP cells, and induced expression of IL-21 in activated mouse CD4+ T cells. This approach is thus a powerful method for producing recombinant proteins in plants.

Cost-effectiveness of sofosbuvir plus ribavirin therapy for hepatitis C virus genotype 2 infection in South Korea.

BACKGROUND AND AIM: For genotype 2 chronic hepatitis C (CHC), the efficacy and safety of sofosbuvir plus ribavirin therapy (SOF + RBV) was better than pegylated interferon plus ribavirin therapy (PR) at a greater drug cost. This study investigated the cost-effectiveness of SOF + RBV compared with PR for treatment-naïve genotype 2 CHC in South Korea. METHODS: Using a decision analytic Markov model, a cost-effectiveness analysis comparing SOF + RBV with PR or no treatment for treatment-naïve genotype 2 CHC was performed with probabilistic and deterministic sensitivity analyses from the payer's perspective in 2017. Three cohorts of patients aged 40-49, 50-59, and 60-69 years were simulated to progress through the fibrosis stages F0-F4 to end-stage liver disease, hepatocellular carcinoma, or death. Published and calculated data on the clinical efficacy of the regimen, health-related quality of life, costs, and transition probabilities were used. RESULTS: While the incremental cost-effectiveness ratio for PR was dominant over no treatment, the incremental cost-effectiveness ratios for SOF + RBV were $20 058 for the patients in their 40s, $19 662 for those in their 50s, and $22 278 for those in their 60s compared with PR. Probabilistic sensitivity analysis indicated an 89.0% probability for the SOF + RBV to be cost-effective at a willingness to pay of $29 754.4 (per-capita gross domestic product in 2017) for the patients in their 40s and 94.1% and 89.1% for the patients in their 50s and 60s, respectively. CONCLUSIONS: The SOF + RBV is a cost-effective option for genotype 2 treatment-naïve CHC patients, especially for the patients with liver cirrhosis in Korea.

Accurate and cost-effective prediction of HBsAg titer in industrial scale fermentation process of recombinant Pichia pastoris by using neural network based soft sensor.

In the current work, the attempt was made to apply best-fitted artificial neural network (ANN) architecture and the respective training process for predicting final titer of hepatitis B surface antigen (HBsAg), produced intracellularly by recombinant Pichia pastoris Mut+ in the commercial scale. For this purpose, in large-scale fed-batch fermentation, using methanol for HBsAg induction and cell growth, three parameters of average specific growth rate, biomass yield, and dry biomass concentration-in the definite integral form with respect to fermentation time-were selected as input vectors; the final concentration of HBsAg was selected for the ANN output. Used dataset consists of 38 runs from previous batches; feed-forward ANN 3:5:1 with training algorithm of backpropagation based on a Bayesian regularization was trained and tested with a high degree of accuracy. Implementing the verified ANN for predicting the HBsAg titer of the five new fermentation runs, excluded from the dataset, in the full-scale production, the coefficient of regression and root-mean-square error were found to be 0.969299 and 2.716774, respectively. These results suggest that this verified soft sensor could be an excellent alternative for the current relatively expensive and time-intensive analytical techniques such as enzyme-linked immunosorbent assay in the biopharmaceutical industry.

Improving the cost effectiveness of enhanced green fluorescent protein production using recombinant Escherichia coli BL21 (DE3): Decreasing the expression inducer concentration.

Green fluorescent protein (GFP) is a globular protein used as biosensor and biomarker in medical and industrial fields. However, due to the expensive production costs of expressing proteins using high-cost inducers like isopropyl-ß-d-1-thiogalactopyranoside (IPTG), the number of GFP applications are still scarce. This work studied the production of enhanced GFP (EGFP) using Escherichia coli BL21 (DE3) [pLysS; pET28(a)], aiming to increase its yield and reduce costs. First, the influence of agitation rate, induction time, and concentration of IPTG in the production of EGFP was evaluated, but only the first two parameters were significant. Subsequently, aiming to reduce costs related to the use of inducer, the IPTG concentration (0.005, 0.010, and 0.025 mM) was decreased and, interestingly, the production levels were maintained or increased. These results show that a proper choice of production conditions, particularly through the decrease of inducer concentration, is effective to reduce the upstream production costs and guarantee high EGFP expression.

A chicken bioreactor for efficient production of functional cytokines.

BACKGROUND: The global market for protein drugs has the highest compound annual growth rate of any pharmaceutical class but their availability, especially outside of the US market, is compromised by the high cost of manufacture and validation compared to traditional chemical drugs. Improvements in transgenic technologies allow valuable proteins to be produced by genetically-modified animals; several therapeutic proteins from such animal bioreactors are already on the market after successful clinical trials and regulatory approval. Chickens have lagged behind mammals in bioreactor development, despite a number of potential advantages, due to the historic difficulty in producing transgenic birds, but the production of therapeutic proteins in egg white of transgenic chickens would substantially lower costs across the entire production cycle compared to traditional cell culture-based production systems. This could lead to more affordable treatments and wider markets, including in developing countries and for animal health applications. RESULTS: Here we report the efficient generation of new transgenic chicken lines to optimize protein production in eggs. As proof-of-concept, we describe the expression, purification and functional characterization of three pharmaceutical proteins, the human cytokine interferon α2a and two species-specific Fc fusions of the cytokine CSF1. CONCLUSION: Our work optimizes and validates a transgenic chicken system for the cost-effective production of pure, high quality, biologically active protein for therapeutics and other applications.

Pharmacoeconomic analysis of treatment of patients infected with hepatitis C virus.

Hepatitis C infection imposes a high economic burden globally. It has been estimated that in 2012, the healthcare cost of Hepatitis C virus (HCV) was $6.5 billion. Furthermore, it has been projected that the cost will reach at $9.1 billion by the year 2024.Frequency of hepatitis C in Pakistan is significantly higher (4.5%) when compared to the populations like India (0.7%), Nepal (1.0), Myanmar (2.5%), Iran (0.8%), China (1%) and Afghanistan (1.1%). The current standard of care for chronic infection with hepatitis C virus is 24 or 48 weeks of therapy with Pegylated interferon-alfa-2a (Peg INF) +Ribavirin (RV) or Interferon alfa-2a (INF) + RV. The objective of this study was to determine that which combination is more effective and the gain in sustained virologic response (SVR) is worth the incremental cost. In total 84 patients were enrolled who received current standard treatment of care for chronic infection with HCV either 24 or 48 weeks of therapy with Peg INF + RV or INF + RV. A pharmacoeconomic analysis was done including fixed and variable cost (comprising concomitant therapies, emergency visits and hospital admissions) of both treatment regimens were calculated and compared with the SVR accomplished by the patients. It was concluded that the Peg INF + RV is cost effective as compared with conventional INF + RV for the treatment of adult patients infected with HCV genotype 3a under a varied array of possibilities regarding treatment costs and effectiveness.

In-house made nucleofection buffer for efficient and cost effective transfection of RAW 264.7 macrophages.

Electroporation is the most widely employed method of gene transfer into macrophages which are hard to transfect. RAW 264.7 is a widely used cell line for studying macrophage responses. Electroporation of RAW 264.7 cells with commercial reagents although very efficient is expensive necessitating the development of cost effective alternatives. In this study, we have formulated an economical electroporation buffer for electroporation of RAW 264.7 cells compatible with commercial nucleofector apparatus. We observed that supplementation of membrane fusogenic agents such as Ficoll, PEG and membrane resealing agent, poloxamer P188, enhanced the transfection efficiency of macrophages to a level comparable to the commercially available solutions thereby providing us a cost effective solution for genetic manipulation of macrophages especially in large numbers.

Optimization of a biotechnological multiproduct batch plant design for the manufacture of four different products: A real case scenario.

In this work a biotechnological multiproduct batch plant that manufactures four different recombinant proteins for human application is described in some detail. This batch plant design is then optimized with regards to the size of equipment using a mixed-integer linear programming (MILP) formulation recently developed by us in order to find a hypothetical new biotechnological batch plant based on the information of real known processes for the production of the four recombinant protein products. The real plant was divided for practical purposes into two sub-processes or facilities: a fermentation facility and a purification facility. Knowing the specific steps conforming the downstream processing of each product, size, and time factors were computed and used as parameters to solve the aforementioned MILP reformulation. New constraints were included to permit the selection of some equipment-such as centrifuges and membrane filters-in a discrete set of sizes. For equipment that can be built according to customer needs-such as reactors-the original formulation was retained. Computational results show the ability of this optimization methodology to deal with real data giving reliable solutions for a multi-product batch plant composed of 44 unit operations in a relatively small amount of time showing that in the case studied it is possible to save up to a 66% of the capital investment in equipment given the cost data used. Biotechnol. Bioeng. 2017;114: 1252-1263. © 2017 Wiley Periodicals, Inc.

Economic impact of ovarian stimulation with corifollitropin alfa versus conventional daily gonadotropins in oocyte donors: a randomized study.

Assisted reproductive technologies are well-established treatments for many types of subfertility representing substantial economic and healthcare implications for patients, healthcare providers and society as a whole. In order to optimize outcomes according to the type of gonadotrophins within an oocyte donor programme, we performed an economic evaluation based on data collected in a multicentre, prospective, randomized study within three private clinics belonging to the IVI Group. Results showed no relevant between-group differences in the clinical variables. According to the economic analysis, ovarian stimulation with corifollitropin alfa increased the overall cost of the treatment as well as the cost per retrieved and effective oocyte, although the differences were not statistically significant. In conclusion, cost savings can be achieved using cheaper gonadotrophins during ovarian stimulation. The cost of corifollitropin alfa compared with recombinant FSH and highly purified human menopausal gonadotrophin should be considered when making treatment decisions.