Rusfertide, a Hepcidin Mimetic, for Control of Erythrocytosis in Polycythemia Vera.

BACKGROUND: Polycythemia vera is a chronic myeloproliferative neoplasm characterized by erythrocytosis. Rusfertide, an injectable peptide mimetic of the master iron regulatory hormone hepcidin, restricts the availability of iron for erythropoiesis. The safety and efficacy of rusfertide in patients with phlebotomy-dependent polycythemia vera are unknown. METHODS: In part 1 of the international, phase 2 REVIVE trial, we enrolled patients in a 28-week dose-finding assessment of rusfertide. Part 2 was a double-blind, randomized withdrawal period in which we assigned patients, in a 1:1 ratio, to receive rusfertide or placebo for 12 weeks. The primary efficacy end point was a response, defined by hematocrit control, absence of phlebotomy, and completion of the trial regimen during part 2. Patient-reported outcomes were assessed by means of the modified Myeloproliferative Neoplasm Symptom Assessment Form (MPN-SAF) patient diary (scores range from 0 to 10, with higher scores indicating greater severity of symptoms). RESULTS: Seventy patients were enrolled in part 1 of the trial, and 59 were assigned to receive rusfertide (30 patients) or placebo (29 patients) in part 2. The estimated mean (±SD) number of phlebotomies per year was 8.7±2.9 during the 28 weeks before the first dose of rusfertide and 0.6±1.0 during part 1 (estimated difference, 8.1 phlebotomies per year). The mean maximum hematocrit was 44.5±2.2% during part 1 as compared with 50.0±5.8% during the 28 weeks before the first dose of rusfertide. During part 2, a response was observed in 60% of the patients who received rusfertide as compared with 17% of those who received placebo (P = 0.002). Between baseline and the end of part 1, rusfertide treatment was associated with a decrease in individual symptom scores on the MPN-SAF in patients with moderate or severe symptoms at baseline. During parts 1 and 2, grade 3 adverse events occurred in 13% of the patients, and none of the patients had a grade 4 or 5 event. Injection-site reactions of grade 1 or 2 in severity were common. CONCLUSIONS: In patients with polycythemia vera, rusfertide treatment was associated with a mean hematocrit of less than 45% during the 28-week dose-finding period, and the percentage of patients with a response during the 12-week randomized withdrawal period was greater with rusfertide than with placebo. (Funded by Protagonist Therapeutics; REVIVE ClinicalTrials.gov number, NCT04057040.).

Thalidomide for Recurrent Bleeding Due to Small-Intestinal Angiodysplasia.

BACKGROUND: Recurrent bleeding from the small intestine accounts for 5 to 10% of cases of gastrointestinal bleeding and remains a therapeutic challenge. Thalidomide has been evaluated for the treatment of recurrent bleeding due to small-intestinal angiodysplasia (SIA), but confirmatory trials are lacking. METHODS: We conducted a multicenter, double-blind, randomized, placebo-controlled trial to investigate the efficacy and safety of thalidomide for the treatment of recurrent bleeding due to SIA. Eligible patients with recurrent bleeding (at least four episodes of bleeding during the previous year) due to SIA were randomly assigned to receive thalidomide at an oral daily dose of 100 mg or 50 mg or placebo for 4 months. Patients were followed for at least 1 year after the end of the 4-month treatment period. The primary end point was effective response, which was defined as a reduction of at least 50% in the number of bleeding episodes that occurred during the year after the end of thalidomide treatment as compared with the number that occurred during the year before treatment. Key secondary end points were cessation of bleeding without rebleeding, blood transfusion, hospitalization because of bleeding, duration of bleeding, and hemoglobin levels. RESULTS: Overall, 150 patients underwent randomization: 51 to the 100-mg thalidomide group, 49 to the 50-mg thalidomide group, and 50 to the placebo group. The percentages of patients with an effective response in the 100-mg thalidomide group, 50-mg thalidomide group, and placebo group were 68.6%, 51.0%, and 16.0%, respectively (P<0.001 for simultaneous comparison across the three groups). The results of the analyses of the secondary end points supported those of the primary end point. Adverse events were more common in the thalidomide groups than in the placebo group overall; specific events included constipation, somnolence, limb numbness, peripheral edema, dizziness, and elevated liver-enzyme levels. CONCLUSIONS: In this placebo-controlled trial, treatment with thalidomide resulted in a reduction in bleeding in patients with recurrent bleeding due to SIA. (Funded by the National Natural Science Foundation of China and the Shanghai Municipal Education Commission, Gaofeng Clinical Medicine; ClinicalTrials.gov number, NCT02707484.).

Pharmacokinetic and Pharmacodynamic Characteristics of Tripegfilgrastim, a Pegylated G-CSF, in Pediatric Patients with Solid Tumors.

A long-acting granulocyte colony-stimulating factor, tripegfilgrastim, was approved in Korea for the prevention of chemotherapy-induced neutropenia in adult patients. In this study, we evaluated the pharmacokinetics, pharmacodynamics, and safety of tripegfilgrastim in pediatric patients. A phase I, open-label, single ascending-dose study was performed in pediatric patients with solid tumors or lymphoma (ClinicalTrials.gov, NCT02963389). The patients were stratified according to age groups (aged 6 to 12 or 12 to 19 years) and received a single subcutaneous dose of tripegfilgrastim 60 µg/kg or 100 µg/kg. Tripegfilgrastim was administered 24 hours after the end of the chemotherapy, and serial blood sampling and safety monitoring were conducted. Twenty-seven patients with solid tumors were enrolled in this study. Tripegfilgrastim was detectable in plasma for an extended period (terminal half-life > 40 hours), and plasma concentrations increased slightly less than dose proportionally. The mean duration of grade 4 neutropenia was reduced as the average tripegfilgrastim concentration during the initial neutrophil recovery process increased. No substantial differences in the pharmacokinetic and pharmacodynamic responses were observed between the two age groups. When stratified by body weight, weighing more than 45 kg has a higher risk of a prolonged neutropenia period when receiving the lower dose (60 µg/kg) of tripegfilgrastim. Tripegfilgrastim was generally safe and well-tolerated in the pediatric patients. These results justify further clinical investigations of tripegfilgrastim at 100 µg/kg dose in pediatric patients.

Rationale and design of the intravenous iron for treatment of anemia before cardiac surgery trial.

Background Approximately 20% to 30% of patients awaiting cardiac surgery are anemic. Anemia increases the likelihood of requiring a red cell transfusion and is associated with increased complications, intensive care, and hospital stay following surgery. Iron deficiency is the commonest cause of anemia and preoperative intravenous (IV) iron therapy thus may improve anemia and therefore patient outcome following cardiac surgery. We have initiated the intravenous iron for treatment of anemia before cardiac surgery (ITACS) Trial to test the hypothesis that in patients with anemia awaiting elective cardiac surgery, IV iron will reduce complications, and facilitate recovery after surgery. Methods ITACS is a 1,000 patient, international randomized trial in patients with anemia undergoing elective cardiac surgery. The patients, health care providers, data collectors, and statistician are blinded to whether patients receive IV iron 1,000 mg, or placebo, at 1-26 weeks before their planned date of surgery. The primary endpoint is the number of days alive and at home up to 90 days after surgery. Results To date, ITACS has enrolled 615 patients in 30 hospitals in 9 countries. Patient mean (SD) age is 66 (12) years, 63% are male, with a mean (SD) hemoglobin at baseline of 118 (12) g/L; 40% have evidence (ferritin <100 ng/mL and/or transferrin saturation <25%) suggestive of iron deficiency. Most (59%) patients have undergone coronary artery surgery with or without valve surgery. Conclusions The ITACS Trial will be the largest study yet conducted to ascertain the benefits and risks of IV iron administration in anemic patients awaiting cardiac surgery.

Comparing the efficacy and side-effects of PDLASTA® (Pegfilgrastim) with PDGRASTIM® (Filgrastim) in breast cancer patients: a non-inferiority randomized clinical trial.

BACKGROUND: The objective of this study was to compare the efficacy and side effects of a single dose (Pegfilgrastim or PDL) or repeated six daily injections (Filgrastim or PDG) during chemotherapy courses in breast cancer patients in a non-inferiority clinical trial. METHODS: In this randomized clinical trial, 80 patients were recruited and allocated randomly to two equal arms. In one group, a single subcutaneous dose of PDL was injected the day after receiving the chemotherapy regimen in each cycle. The second arm received a subcutaneous injection of PDG for six consecutive days in each cycle of treatment. The side effects of GCF treatment and its effect on blood parameters were compared in each cycle and during eight cycles of chemotherapy. RESULTS: Hematologic parameters showed no significant differences in any of the treatment courses between the two study groups. The comparison of WBC (p = 0.527), Hgb (p = 0.075), Platelet (p = 0.819), Neutrophil (p = 0.575), Lymphocyte (p = 705) and ANC (p = 0.675) changes during the eight courses of treatment also revealed no statistically significant difference between the two study groups. Side effects including headache, injection site reaction and muscle pain had a lower frequency in patients receiving PDL drugs. CONCLUSION: It seems that PDL is non-inferior in efficacy and also less toxic than PDG. Since PDL can be administered in a single dose and is also less costly, it can be regarded as a cost-effective drug for the treatment of chemotherapy-induced neutropenia. TRIAL REGISTRATION: IRCT20190504043465N1 , May 2019.

Uptake and cost of biosimilar filgrastim among Medicare and Medicaid populations in 2015-2018.

BACKGROUND: The first biosimilar product filgrastim-sndz was approved by the FDA in 2015, but real-world evaluations of its uptake and cost in nationally representative populations are limited. OBJECTIVE: To evaluate the uptake and cost of filgrastim-sndz, relative to its originator filgrastim and alternative biologic tbofilgrastim, among Medicare and Medicaid populations. METHODS: Using the annually aggregated, product-level utilization and cost data of biologic and biosimilar filgrastim products in 2015-2018 from CMS drug spending data, total number of claims and costs for all 3 filgrastim products were identified and extracted for Medicare Part B, Part D, and Medicaid reimbursement. Annual average cost per claim and per beneficiary of individual filgrastim products were also extracted, and their annual growth rates were calculated. RESULTS: Three years after entering the US market, use of filgrastim-sndz increased to 49.1% and 46.0% of all filgrastim claims paid by Medicare Parts B and D, respectively, and to 38.7% of filgrastim Medicaid claims in 2018. Total cost for filgrastim-sndz also reached 42.8%, 41.8%, and 26.9% of all filgrastim products paid by Medicare Parts B and D and Medicaid, respectively. Significant reductions in average cost per claim for filgrastim-sndz in 2017 and 2018 were observed in Medicare Part B and Medicaid. CONCLUSIONS: Significant uptake of biosimilar filgrastim in Medicare and Medicaid programs occurred during the first 3 years of marketing. Policymakers may use the evidence to evaluate existing barriers and policies regarding biosimilar adoption. DISCLOSURES: No outside funding supported this work. The author has no conflicts of interest to disclose.

Dual therapy with an oral non-vitamin K antagonist and a P2Y12 inhibitor vs triple therapy with aspirin, a P2Y12 inhibitor and a vitamin K antagonist for the treatment of diabetes mellitus patients with co-existing atrial fibrillation following percutaneous coronary intervention: A meta-analysis.

BACKGROUND: In this analysis, we aimed to compare the efficacy and safety of dual therapy (DT) with a non-vitamin K oral anticoagulant (NOAC) and an adenosine diphosphate receptor antagonist (P2Y12 inhibitor) vs triple therapy (TT) with aspirin, a P2Y12 inhibitor and a vitamin K antagonist for the treatment of diabetes mellitus (DM) patients with co-existing atrial fibrillation (AF) following percutaneous coronary intervention (PCI). METHODS: Medical Literature Analysis and Retrieval System Online (MEDLINE), http://www.ClinicalTrials.gov, Excerpta Medical data BASE (EMBASE), Web of Science, Cochrane Central and Google Scholar were the searched databases. Studies that were randomized trials or observational studies comparing DT vs TT for the treatment of DM patients with co-existing AF following PCI were included in this analysis. The adverse cardiovascular outcomes and bleeding events were the endpoints. This meta-analysis was carried out by the RevMan version 5.4 software. Risk ratios (RR) with 95% confidence intervals (CI) were used to represent data and interpret the analysis. RESULTS: A total number of 4970 participants were included whereby 2456 participants were assigned to the DT group and 2514 participants were assigned to the TT group. The enrollment period varied from year 2006 to year 2018. Our current results showed that major adverse cardiac events (RR: 1.00, 95% CI: 0.84-1.20; P = .98), mortality (RR: 1.08, 95% CI: 0.78-1.48; P = .66), myocardial infarction (RR: 1.02, 95% CI: 0.74-1.42; P = .90), stroke (RR: 0.94, 95% CI: 0.53-1.67; P = .84) and stent thrombosis (RR: 1.09, 95% CI: 0.56-2.10; P = .80) were similar with DT versus TT in these patients. However, the risks for total major bleeding (RR: 0.66, 95% CI: 0.54-0.82; P = .0001), total minor bleeding (RR: 0.74, 95% CI: 0.64-0.85; P = .0001), Thrombolysis in Myocardial Infarction (TIMI) defined major bleeding (RR: 0.58, 95% CI: 0.35-0.95; P = .03), TIMI defined minor bleeding (RR: 0.62, 95% CI: 0.42-0.92; P = .02), intra-cranial bleeding (RR: 0.34, 95% CI: 0.13-0.95; P = .04) and major bleeding defined by the International Society on Thrombosis and Hemostasis (RR: 0.68, 95% CI: 0.51-0.90; P = .008) were significantly higher with TT. CONCLUSIONS: DT with a NOAC and a P2Y12 inhibitor was associated with significantly less bleeding events without increasing the adverse cardiovascular outcomes when compared to TT with aspirin, a P2Y12 inhibitor and a Vitamin K antagonist for the treatment of DM patients with co-existing AF following PCI. Hence, DT is comparable in efficacy, but safer compared to TT. This interesting hypothesis will have to be confirmed in future studies.

Effect of lipegfilgrastim administration as prophylaxis of chemotherapy-induced neutropenia on dose modification and incidence of neutropenic events: real-world evidence from a non-interventional study in Belgium and Luxembourg.

Objectives: This study evaluated the effect of lipegfilgrastim, a glycopegylated granulocyte-colony stimulating factor, used as primary (PP) or secondary prophylaxis (SP) on chemotherapy (CT) treatment modifications, as well as the incidence of CT-induced neutropenic events in adult patients receiving cytotoxic CT with or without biological therapy (BT) for solid and hematological tumors, in routine clinical practice. Other objectives were to characterize the population of lipegfilgrastim-treated cancer patients and safety assessment. Methods: This phase 4, prospective, observational study was conducted at 15 centers from Belgium and Luxembourg, between 2015 and 2017. Results: Of 139 patients, 82.7% had breast cancer and 54.7% were treated with dose-dense regimens. Most received lipegfilgrastim as PP (82.0%) and were at high-risk of febrile neutropenia (FN) (68.3%). FN and grade III/IV neutropenia were reported for 7.9% and 22.3% patients. Among 123 evaluated patients, CT/BT dose modifications were recorded for 33.3% (PP) and 52.4% (SP) of patients receiving lipegfilgrastim; dose reductions, followed by dose delays, were more frequent than omissions. Among 45 patients with dose modifications, FN was reported for 8.8% and 9.1% patients and grade IV neutropenia for 17.6% and 18.2% of patients when lipegfilgrastim was applied for PP and SP, respectively. Adverse events related to lipegfilgrastim occurred for 55 (39.6%) patients; bone pain and back pain were more frequent. Lipegfilgrastim-related serious adverse events were reported for 9 (6.5%) patients. Conclusion: Use of lipegfilgrastim in real-world settings resulted in limited CT dose modifications and low incidences of neutropenic events, with no new safety concerns arising.

Biosimilarity Assessment of 2 Filgrastim Therapeutics in Healthy Volunteers.

This study aimed to compare the pharmacokinetic, pharmacodynamic, and safety profiles of a proposed biosimilar and innovator filgrastim therapeutics in healthy volunteers. In a crossover design, 23 subjects received a single subcutaneous injection of 300-µg filgrastim, followed by a 7-day washout period. Assessed pharmacokinetic parameters were the maximum observed filgrastim serum concentration (Cmax ), time to reach Cmax (tmax ), the area under the concentration-time curve (AUC), and elimination half-life. Pharmacodynamics were assessed by the maximum observed absolute neutrophil count effect (Emax ), tmax,E (time to reach Emax ), and the area under the effect of the absolute neutrophil count -time curve. The test/reference ratio (90% confidence intervals) of Cmax of 0.992 (0.860-1.143), AUC0-inf of 0.995 (0.891-1.111), Emax of 0.952 (0.841, 1.078), and area under the effect of the absolute neutrophil count -time curve from time zero to 96 hours of 0.939 (0.854-1.032), were all well within the predefined equivalence boundaries of 80% and 125%. Obtained values for tmax (∼4 hours), tmax,E (∼15 hours), and elimination half-life (∼3.5 hours) were comparable between 2 treatment groups. The local tolerability and incidence of adverse events were comparable, with no clinically meaningful difference between biosimilar and innovator products. Altogether, the results suggested a high similarity of the proposed biosimilar to the innovator filgrastim in healthy volunteers.

Justification for a Fixed Dose of Eflapegrastim, a Long-Acting G-CSF, in Patients Receiving Docetaxel-Cyclophosphamide Chemotherapy.

Eflapegrastim (Rolontis) is a long-acting granulocyte colony-stimulating factor (G-CSF) produced by conjugating a human G-CSF analogue and a human immunoglobulin G4 Fc fragment, linked via a polyethylene glycol linker. Weight-based doses of 45 to 270 µg/kg eflapegrastim (12.3-73.6 µg/kg as G-CSF) were evaluated in a phase 2 study in patients. Based on these results, a fixed dose of 13.2 mg eflapegrastim (3.6 mg G-CSF) was compared with pegfilgrastim (6 mg G-CSF) in 2 phase 3 studies and in a pharmacokinetic single-arm multicenter study. Absolute neutrophil count (ANC) data from these 3 studies were evaluated in patients with early-stage breast cancer who were treated with docetaxel and cyclophosphamide (n = 669). Serum concentrations of eflapegrastim were determined by enzyme-linked immunosorbent assay. Eflapegrastim systemic exposures were higher in cycle 1 than in cycle 3, likely attributable to the higher ANC in cycle 3, increasing neutrophil-mediated clearance. Eflapegrastim elicited a greater effect on ANC than pegfilgrastim in patients at ∼60% of the G-CSF dose. Body weight had no clinically significant effect on response, justifying administration of a fixed dose of eflapegrastim. The results from 2 phase 3 studies demonstrate that eflapegrastim at a fixed dose of 13.2 mg (3.6 mg G-CSF) administered once per chemotherapy cycle is effective in prophylactic treatment of chemotherapy-induced neutropenia.

Voxelotor: A Novel Treatment for Sickle Cell Disease.

OBJECTIVE: To review the pharmacological characteristics, clinical evidence, and place in therapy of voxelotor for the treatment of sickle cell disease (SCD). DATA SOURCES: A comprehensive literature search of PubMed (1966 to April 2020) was conducted. Key search terms included GBT440, sickle cell, and voxelotor. Other sources were derived from bibliographies of articles, product labeling, manufacturer's website, and news releases. ClinicalTrials.gov was searched for additional studies. STUDY SELECTION AND DATA EXTRACTION: All English-language articles identified from the data sources were reviewed and evaluated. Case reports/series and phase 1 through 3 clinical trials were included. DATA SYNTHESIS: SCD is an inherited disorder associated with significant morbidity and early mortality. Three medications approved for SCD reduce SCD-associated complications but do not selectively ameliorate the underlying disease. Voxelotor is a novel agent that targets the pathophysiology of SCD. A phase 3 trial reported an increase in mean Hb level from baseline for voxelotor compared with placebo (1.1 vs -0.1 g/dL; P < 0.001). Voxelotor is generally well tolerated, with common adverse effects including headache, diarrhea, nausea, and arthralgia. RELEVANCE TO PATIENT CARE AND CLINICAL PRACTICE: Voxelotor may be considered for patients with SCD who have continued anemia and hemolysis despite being on maximum tolerated dose of hydroxyurea or in those who are hydroxyurea intolerant. Voxelotor is costly; therefore, both cost and benefit should be weighed before prescribing. CONCLUSION: Voxelotor appears to be safe and effective as monotherapy or in combination with hydroxyurea for patients with SCD who are 12 years of age and older.

Why does activated partial thromboplastin time prolongation occur in severe fever with thrombocytopenia syndrome?

Severe fever with thrombocytopenia syndrome (SFTS) is caused by infection with SFTS virus and this mortality rate is 16.2% to 30%. An 85-year-old male patient presented to the emergency department of the hospital with primary complaints of fever and consciousness disturbance. Haemophagocytic syndrome and prolonged activated partial thromboplastin time (APTT) without associated prolonged prothrombin time were observed, suggesting SFTS, which was eventually diagnosed. APTT-only prolongation has been reported previously with SFTS, but the mechanism is unknown. The absence of coagulation factors was determined by a cross-mixing study. In addition, examination of intrinsic coagulation factors showed reduced factor XI activity. These results suggest that factor XI is causally related to APTT-only prolongation in SFTS.

Filgrastim induced thrombocytopenia.

Drug-induced thrombocytopenia (DITP) is suggested by severe thrombocytopenia with subsequent recovery of platelet count after removal of the offending drug. The diagnosis is ascertained when there is reproducibility of thrombocytopenia with repeated exposure. Filgrastim is used during peripheral blood progenitor cell harvest during autologous stem cell transplantation in the setting of multiple myeloma to prolong event-free survival and overall mortality. The following case illustrates all of the suggestive features of DITP after filgrastim exposure during elective stem cell harvest. Due to the inability to tolerate filgrastim, autologous stem cell transplant was aborted in this patient and he was maintained on induction chemotherapy.

Association of NUDT15*3 and FPGS 2572C>T Variants with the Risk of Early Hematologic Toxicity During 6-MP and Low-Dose Methotrexate-Based Maintenance Therapy in Indian Patients with Acute Lymphoblastic Leukemia.

Genetic variants influencing the pharmacokinetics and/or pharmacodynamics of the chemotherapeutic drugs used in Acute Lymphoblastic Leukemia (ALL) therapy often contribute to the occurrence of treatment related toxicity (TRT). In this study, we explored the association of candidate genetic variants with early hematological TRT (grade 3-4) occurring within the first 100 days of low-dose methotrexate and 6-mercaptopurine based maintenance therapy (n = 73). Fourteen variants in the following candidate genes were genotyped using allele discrimination assay by real-time PCR: ABCB1, DHFR, GGH, FPGS, MTHFR, RFC1, SLCO1B1, TPMT, and NUDT15. Methotrexate polyglutamate (MTXPG3-5) levels in red blood cells were measured by LC-MS/MS. Early hematological TRT (grade 3-4) was seen in 54.9% of patients. The NUDT15*3 allele was associated with early TRT occurrence [HR: 3.04 (95% CI: 1.5-6.1); p = 0.007]. Sensitivity of early TRT prediction improved (from 30.7% to 89.7%) by considering FPGS variant (rs1544105) carrier status along with NUDT15*3 allele [HR = 2.7 (1.5-4.7, p = 0.008)]. None of the considered genetic variants were associated with MTXPG3-5 levels, which in turn were not associated with early TRT. NUDT15*3 allele carrier status could be used as a stratifying marker for Indian ALL patients to distinguish patients at high or low risk of developing early hematological TRT.

Biosimilar Uptake in Medicare Part B Varied Across Hospital Outpatient Departments and Physician Practices: The Case of Filgrastim.

OBJECTIVES: To examine the uptake of filgrastim-sndz (Zarxio), the first biosimilar to launch in the United States, in the Medicare Part B fee-for-service program from its launch in September 2015 to December 2017 and compare characteristics of patients and facilities that used filgrastim-sndz or originator filgrastim (Neupogen). METHODS: The 20% sample of Medicare Part B fee-for-service administrative claims data was used to extract information on claims for any filgrastim product between January 1, 2015 and December 31, 2017. RESULTS: The utilization of filgrastim-sndz in Medicare Part B increased sharply between January and August 2016, surpassing filgrastim by November 2017, contributing to a 30% decrease in overall spending on this drug since 2015. Uptake was faster and larger in physician practices compared with hospital outpatient departments. About 77% of patients receiving filgrastim-sndz were new users. Utilization patterns indicated that product selection occurred at the facility level, rather than being at the discretion of the prescribing physician or driven by patient characteristics. CONCLUSION: Uptake of biosimilar filgrastim in the Medicare Part B program occurred despite multiple challenges to the adoption of biosimilars in the US market, suggesting that substantial potential savings could be generated by improving biosimilar uptake. Our findings indicated that physician practices and hospital outpatient departments have distinctive biosimilar uptake patterns. Thus policy makers aiming to contain Medicare Part B spending might consider focusing on incentivizing biosimilar uptake among hospital outpatient departments.

Economic modeling for the US of the cost-efficiency and associated expanded treatment access of conversion to biosimilar pegfilgrastim-bmez from reference pegfilgrastim.

Aims: For this economic analysis, we aimed to model: (1) the cost-efficiency of prophylaxis with biosimilar pegfilgrastim-bmez for chemotherapy-induced (febrile) neutropenia (CIN/FN) compared to reference pegfilgrastim, and (2) the expanded access to CIN/FN prophylaxis and anti-neoplastic treatment that could be achieved with biosimilar cost-savings on a budget-neutral basis.Methods: In a hypothetical panel of 20,000 cancer patients receiving CIN/FN prophylaxis and using the average sales price (ASP) for the second quarter of 2019 for reference pegfilgrastim, we: conducted an ex ante simulation from the payer perspective of the cost-savings of 10-100% conversion from reference to biosimilar pegfilgrastim-bmez using drug price discounting ranging from 10-35%; estimated the budget-neutral expanded access to biosimilar pegfilgrastim-bmez enabled by these cost-savings; and estimated the budget-neutral expanded access to anti-neoplastic treatment with pembrolizumab. The simulations were replicated using fourth quarter 2019 wholesale acquisition cost (WAC) for reference pegfilgrastim and biosimilar pegfilgrastim-bmez in a post facto analysis.Results: In ASP simulations, cost-savings of using pegfilgrastim-bmez over reference pegfilgrastim in a 20,000 patient panel range from $1.3 M (at 15% price discount) to $3 M (35%) at 10% conversion rate and from $6.4 M to $14.9 M, respectively, at 50% conversion. These savings could provide prophylaxis with pegfilgrastim-bmez to an additional 352 (15% discount) to 1,076 patients (35%) at 10% conversion or 1,764-5,384, respectively, at 50% conversion. Alternatively, savings could be reallocated for anti-neoplastic treatment with pembrolizumab to 3 (15% discount) to 9 (35%) patients at 10% conversion or 19-45, respectively, at 50% conversion. When utilizing WAC, cost-savings range from $4.6 M (10% conversion) to $23.1 M (50%) which could provide pegfilgrastim-bmez to an additional 1,174 (10% conversion) to 5,873 patients (50%).Conclusions: Prophylaxis with biosimilar pegfilgrastim-bmez increases the value of cancer care by generating significant cost-savings that could be reallocated to provide expanded access to CIN/FN prevention and anti-neoplastic therapy on a budget-neutral basis.

Systematic Review of Voxelotor: A First-in-Class Sickle Hemoglobin Polymerization Inhibitor for Management of Sickle Cell Disease.

Voxelotor, a sickle hemoglobin polymerization inhibitor, was approved by the U.S. Food and Drug Administration to treat sickle cell disease (SCD) in November 2019. This article reviews published data about voxelotor treatment of SCD based on a search of MEDLINE, Embase, and International Pharmaceutical Abstracts. In a phase I/II trial, voxelotor demonstrated a dose-dependent pharmacokinetic and pharmacodynamic response and was well tolerated in healthy volunteers and patients with SCD. In a multi-center, randomized, double-blind, phase III trial (HOPE trial), a significantly higher percentage of patients randomized to voxelotor had increased hemoglobin (> 1 g/dl from baseline) compared to placebo. A greater reduction of hemolytic markers was also observed in the voxelotor-treated group, whereas the incidence of adverse effects was comparable. Three case series or reports also demonstrated the efficacy and safety of voxelotor use in a limited number of SCD patients in the real-world situation, although one patient with SCD, severe anemia, and a history of autoantibody-mediated hemolysis failed to respond to voxelotor. An ongoing trial (HOPE-KIDS) is designed to establish the use of voxelotor in younger pediatric patients with SCD. There is a theoretical concern that voxelotor may impair oxygen delivery, due to modification of the oxygen affinity of hemoglobin, which needs to be further evaluated. As a first-in-class hemoglobin modulator, voxelotor offers a new treatment option targeting the root cause of SCD.