Cognition and education benefits of increased hemoglobin and blood oxygenation in children with sickle cell disease

BACKGROUND: Among individuals with sickle cell disease (SCD), decreased hemoglobin is associated with lower oxygen saturation (SpO2) and increased risk of stroke, both of which are associated with lower intelligence quotient (IQ) scores. Thus, increasing hemoglobin and SpO2 in individuals with SCD may increase IQ and educational attainment. METHODS: A cohort simulation model was built to determine academic performance and educational attainment based on cognitive function (measured by IQ) of a pediatric SCD cohort randomly assigned to treatment and control groups. The model contained two key stages: childhood (\u3c10 years) and adolescence (≥10 years). In stage 1, increased hemoglobin and increased SpO2 (assigned to the treatment group) were determinants of higher IQ, prevention of IQ deterioration over time. Increased hemoglobin was also a determinant of decreased stroke risk. In stage 2, improvement in adolescent IQ as a result of treatment was a determinant of academic performance. RESULTS: In a simulated cohort of 2000 children and adolescents with SCD (52.5% female, 50% treated), stroke incidence was predicted to be 44.4% lower among the treated group than the untreated group (4.5% versus 8.1%, respectively). The average IQ among the treated group was estimated to be 91.1 compared with 82.9 in the untreated group (a 9.9% difference; P\u3c0.001). Finally, high school (≥12 years of education) completion rates were estimated to be 64.7% higher among the treated group: 76.1% of the treated group was projected to complete high school compared with 46.2% of the untreated group. CONCLUSIONS: Our model predicts that an average improvement in hemoglobin of 1.1 g/dL (11 g/L) among individuals with SCD may be associated with improved neurocognition and educational outcomes. These improvements may also generate benefits not captured by our model, including improved quality of life, employment, and income

Impact of voxelotor (GBT440) on unconjugated bilirubin and jaundice in sickle cell disease

For many patients with sickle cell disease (SCD), jaundice is a significant clinical disease manifestation that impacts on patient well-being. We report a case of a patient with SCD and chronic jaundice treated with voxelotor (GBT440), a novel small molecule hemoglobin oxygen affinity modulator and potential disease-modifying therapy for SCD. The case patient is a 27- year-old Black male with a long history of SCD with clinical jaundice and scleral icterus. After starting voxelotor, the patient reported that his jaundice cleared within one week, and that he felt much better with more energy, and was relieved after his eyes cleared. Voxelotor reduced bilirubin and unconjugated bilirubin (by up to 76%), and hemoglobin improved from 9.9 g/dL at baseline to 11.1 g/dL at 90 days. Jaundice impacts many adults with SCD, significantly impacting self-image. Voxelotor treatment reduced bilirubin levels and improved jaundice, resulting in an improved sense of well-being in our case patient

Denosumab for Elderly Men with Osteoporosis: A Cost-Effectiveness Analysis from the US Payer Perspective

Purpose. To evaluate the cost-effectiveness of denosumab versus other osteoporotic treatments in older men with osteoporosis from a US payer perspective. Methods. A lifetime cohort Markov model previously developed for postmenopausal osteoporosis (PMO) was used. Men in the model were 78 years old, with a BMD T-score of −2.12 and a vertebral fracture prevalence of 23%. During each 6-month Markov cycle, patients could have experienced a hip, vertebral or nonhip, nonvertebral (NHNV) osteoporotic fracture, remained in a nonfracture state, remained in a postfracture state, or died. Background fracture risks, mortality rates, persistence rates, health utilities, and medical and drug costs were derived from published sources. Previous PMO studies were used for drug efficacy in reducing fracture risk. Lifetime expected costs and quality-adjusted life-years (QALYs) were estimated for denosumab, generic alendronate, risedronate, ibandronate, teriparatide, and zoledronate. Results. Denosumab had an incremental cost-effectiveness ratio (ICER) of $16,888 compared to generic alendronate and dominated all other treatments. Results were most sensitive to changes in costs of denosumab and the relative risk of hip fracture. Conclusion. Despite a higher annual treatment cost compared to other medications, denosumab is cost-effective compared to other osteoporotic treatments in older osteoporotic US men

Low hemoglobin increases risk for cerebrovascular disease, kidney disease, pulmonary vasculopathy, and mortality in sickle cell disease: A systematic literature review and meta-analysis.

Sickle cell disease (SCD) is characterized by deoxygenation-induced polymerization of hemoglobin in red blood cells, leading to hemolytic anemia, vaso-occlusion, and the development of multiple clinical complications. To characterize the clinical burden associated with differences in hemoglobin concentration and hemolysis measures, a systematic literature review of MEDLINE, EMBASE, and related meta-analyses was undertaken. For quantitative analyses related to hemoglobin concentration, pooled results were analyzed using random effects models to control for within-and between-study variability. To derive risk ratios associated with hemoglobin concentration change, we combined ratios of means from select studies, which reported hazard and odds ratios in meta-analyses for hemoglobin concentration-related outcomes and changes between groups. Forty-one studies were identified for inclusion based on relating hemoglobin concentration to clinical outcomes. Meta-analyses demonstrated that mean hemoglobin concentration was significantly lower in patients with cerebrovascular disease (0.4 g/dL), increased transcranial Doppler velocity in cerebral arteries (0.6 g/dL), albuminuria (0.6 g/dL), elevated estimated pulmonary artery systolic pressure (0.9 g/dL), and in patients that subsequently died (0.6 g/dL). In a risk reduction meta-analysis, modeled increased hemoglobin concentrations of 1 g/dL or greater resulted in decreased risk of negative clinical outcomes of 41% to 64%. In conclusion, chronic anemia is associated with worse clinical outcomes in individuals with SCD and even modest increases in hemoglobin concentration may be beneficial in this patient population. This systematic review has been registered on Prospero (Registration number CRD42018096860; https://www.crd.york.ac.uk/prospero/)

Low hemoglobin increases risk for cerebrovascular disease, kidney disease, pulmonary vasculopathy, and mortality in sickle cell disease: A systematic literature review and meta-analysis.

Sickle cell disease (SCD) is characterized by deoxygenation-induced polymerization of hemoglobin in red blood cells, leading to hemolytic anemia, vaso-occlusion, and the development of multiple clinical complications. To characterize the clinical burden associated with differences in hemoglobin concentration and hemolysis measures, a systematic literature review of MEDLINE, EMBASE, and related meta-analyses was undertaken. For quantitative analyses related to hemoglobin concentration, pooled results were analyzed using random effects models to control for within-and between-study variability. To derive risk ratios associated with hemoglobin concentration change, we combined ratios of means from select studies, which reported hazard and odds ratios in meta-analyses for hemoglobin concentration-related outcomes and changes between groups. Forty-one studies were identified for inclusion based on relating hemoglobin concentration to clinical outcomes. Meta-analyses demonstrated that mean hemoglobin concentration was significantly lower in patients with cerebrovascular disease (0.4 g/dL), increased transcranial Doppler velocity in cerebral arteries (0.6 g/dL), albuminuria (0.6 g/dL), elevated estimated pulmonary artery systolic pressure (0.9 g/dL), and in patients that subsequently died (0.6 g/dL). In a risk reduction meta-analysis, modeled increased hemoglobin concentrations of 1 g/dL or greater resulted in decreased risk of negative clinical outcomes of 41% to 64%. In conclusion, chronic anemia is associated with worse clinical outcomes in individuals with SCD and even modest increases in hemoglobin concentration may be beneficial in this patient population. This systematic review has been registered on Prospero (Registration number CRD42018096860; https://www.crd.york.ac.uk/prospero/)

Real-world effectiveness of voxelotor for treating sickle cell disease in the US: a large claims data analysis

Sickle cell disease (SCD) is a genetic disease that impacts patients' quality of life, healthcare costs, and life expectancy. Elevated sickle hemoglobin (HbS), which readily polymerizes, causes red blood cell sickling, leading to chronic hemolytic anemia and complications often requiring hospitalization and transfusions. In 2019, voxelotor, which inhibits HbS polymerization, was approved for SCD treatment. This study uses real-world evidence to assess voxelotor's effectiveness in SCD patients in typical clinical practice from 2019 to 2021 using a national medical claims database (N = 3128). After initiating voxelotor, 60.8% of patients with available hemoglobin (Hb) laboratory data (n = 74) showed a Hb increase >1 g/dL. Mean transfusion rate per patient-year dropped 52% in patients with ≥1 transfusion before treatment (n = 190). In patients with ≥1 of the corresponding events (n = 1065), decreases were observed in mean vaso-occlusive crisis (VOC) frequency (-23%); mean VOC-related hospitalizations and length of stay (LOS) time (-34% and -30%, respectively); mean all-cause hospitalization and LOS time (-37% and -23%, respectively); outpatient visits (-10%); iron chelation use (-46%); and prescribed opioids (-13%). These data align with randomized controlled trial results showing voxelotor improvements and support that voxelotor may lower transfusion and VOC rates in clinical practice

Real-World Experience of Voxelotor for the Management of Complications in Sickle Cell Disease

Abstract Background: Sickle cell disease (SCD) is an inherited systemic disorder characterized by chronic hemolytic anemia and recurrent vaso-occlusion, which can lead to acute and chronic complications, disability, and early mortality. Patients with SCD are hospitalized frequently and most commonly for vaso-occlusive crises (VOCs). Furthermore, most will require a blood transfusion for prevention or acute management of complications, with >90% of adults receiving ≥1 transfusion in their lifetime. Voxelotor (Oxbryta ®) tablets are indicated for treatment of SCD in adults and adolescents aged ≥12 years. Emerging evidence shows that voxelotor, an oral, once-daily sickle hemoglobin-polymerization inhibitor, may improve the clinical symptoms of SCD and reduce VOC rates as well as the need for transfusions. This study sought to assess the real-world impact of voxelotor treatment on the rates and management of SCD-related complications. Methods: Medical and pharmacy claims data for patients aged ≥12 years with SCD who initiated voxelotor therapy between November 2019 and March 2021 were procured from the Symphony Health claims database. Patients with ≥1 year's data before the index date (date of the first voxelotor claim for each patient) were included in the analyses. Baseline demographic and clinical characteristics were summarized using descriptive and inferential statistics. Annualized rates per patient-year (PPY) for transfusions, VOCs, VOC-related and all-cause hospitalizations, before and after voxelotor initiation were compared. Hemoglobin (Hb) responses were evaluated for a subset of patients for whom Hb lab data were available (≥1 Hb value recorded 30 days before initiating voxelotor and ≥1 Hb value recorded after the index date). Results: As of March 2021, a total of 2695 eligible patients from the Symphony Health claims database were included in the analysis (mean age: 34.6 years; 60% female); 915 patients (34%) had ≥1 VOC in the 3 months before initiating voxelotor. Among the subset of patients with pre- and post-voxelotor Hb measurements (n=63), mean (95% CI) Hb was 7.9 (7.5-8.2) g/dL at baseline, and final Hb was 8.9 (8.4-9.4) g/dL after voxelotor initiation. Most patients (38/63; 60.3%) achieved a Hb increase of >1 g/dL at any time point during follow-up. In 357 patients who received ≥1 transfusion in the year before voxelotor initiation, the mean (95% CI) transfusion rate decreased by 43%, from 3.2 (2.8-3.7) to 1.8 (1.4-2.3) PPY (P<0.001) (Table). In 40 patients receiving chronic transfusions (≥8), the mean (95% CI) transfusion rate decreased by 34%, from 9.8 (8.3-11.4) to 6.5 (4.4-8.5) PPY (P=0.007). Among patients who had ≥1 VOC in the 3 months before initiating voxelotor, the mean (95% CI) annualized VOC rate decreased by 22%, from 10.9 (10.4-11.5) to 8.5 (7.8-9.3) (P<0.001); and the mean (95% CI) rate of VOC-related hospitalizations decreased by 32%, from 7.3 (6.9-7.7) to 5.0 (4.4-5.6) (P<0.001). In 636 patients who were previously hospitalized in the 3 months before voxelotor initiation, the mean (95% CI) all-cause hospitalization rate reduced by 36%, from 7.5 (7.1-7.9) to 4.8 (4.3-5.3) (P<0.001) after treatment. Limitations of this analysis include the possibility of secular trend biases or general regression to the mean. Conclusions: In real-world practice, voxelotor increased Hb by ≥1 g/dL, consistent with the HOPE trial. Data suggest statistically significant reductions in transfusions, VOCs, all-cause and VOC-related hospitalizations after voxelotor use. This real-world evidence provides additional support for the use of voxelotor in the treatment of hemolytic anemia and the management of its associated complications. Figure 1 Figure 1. Disclosures Shah: Novartis: Research Funding, Speakers Bureau; Emmaus: Consultancy; Alexion: Speakers Bureau; GLG: Consultancy; GBT: Consultancy, Research Funding, Speakers Bureau; Guidepoint Global: Consultancy; Bluebird Bio: Consultancy; CSL Behring: Consultancy. Lipato: Global Blood Therapeutics: Speakers Bureau. Alvarez: Forma Therapeutics: Membership on an entity's Board of Directors or advisory committees; GBT: Membership on an entity's Board of Directors or advisory committees. Delea: Global Blood Therapeutics: Research Funding; Amgen: Research Funding; Bristol-Myers Squibb: Research Funding; Celgene: Research Funding; Takeda: Research Funding; Merck: Research Funding; Policy Analysis Inc.: Current Employment; AbbVie: Research Funding; Novartis: Research Funding; Regeneron: Research Funding; Sanofi: Research Funding. Lonshteyn: Policy Analysis Inc. (PAI): Current Employment; Global Blood Therapeutics: Research Funding; Novartis: Research Funding. Weycker: Policy Analysis Inc. (PAI): Current Employment, Current equity holder in publicly-traded company; Global Blood Therapeutics: Research Funding; Novartis: Research Funding. Nguyen: Global Blood Therapeutics: Current Employment, Current equity holder in publicly-traded company. Beaubrun: Global Blood Therapeutics: Current Employment, Current equity holder in publicly-traded company. Agodoa: Global Blood Therapeutics: Current Employment, Current equity holder in publicly-traded company

Real-World Effectiveness of Voxelotor for Treating Sickle Cell Disease in the US

Background: Until late 2019, few treatments had been approved by the FDA for treating sickle cell disease (SCD). Voxelotor (Oxbryta®) is a sickle hemoglobin-polymerization inhibitor approved by the FDA in November 2019 for treatment of SCD in adults and adolescents aged ≥12 years under an accelerated approval based on results of the pivotal HOPE study. In HOPE, voxelotor increased average hemoglobin (Hb) by 1.1 g/dL from baseline in patients with 1-10 vaso-occlusive crises (VOCs) in the previous year and a Hb level between 5.5 and 10.5 g/dL who were not transfusion dependent. Of the participants on voxelotor 1500 mg, 51% had a Hb response >1.0 g/dL at week 24 (Vichinsky et al, NEJM 2019). This study sought to assess the real-world effectiveness of voxelotor based on data during the first 6 months post FDA approval. Methods: Data on medical and pharmacy claims for patients who were aged ≥12 years and receiving voxelotor from December 2019 to May 2020 were obtained from the Symphony Health claims dataset. For each patient, the date of the first voxelotor claim was defined as the "index date." Patients with at least 1 year's data prior to the index date were included in the analyses. Patients' demographic and clinical characteristics were summarized descriptively. Standardized annualized rates of transfusions and VOCs per patient per year (PPPY) prior to and after voxelotor initiation were compared. A subset of patients in the Symphony Health claims dataset had Hb lab data available. Patients with at least 1 Hb result within 30 days prior to the index date and at least 1 Hb result after the index date were included for Hb analyses. For these patients, change in Hb and the percentage of patients achieving a >1 g/dL increase in Hb were summarized. Confidence intervals and P values for changes in outcomes were based on bootstrapping. Results: As of May 31, 2020, 1275 patients from the Symphony Health claims datasets were identified who received voxelotor (40% male, mean age 35.7 years). In the year prior to voxelotor initiation, 715 (56.1%) of these patients received hydroxyurea, 121 (9.5%) received L-glutamine, 166 (13.0%) received at least 1 transfusion, 17 (1.3%) were on chronic transfusion (≥8 transfusions per year), and 681 (53.4%) had 1 or more VOCs. Mean (SD) follow-up was 64.9 (40.7) days. Among 1275 patients, 175 and 52 patients had at least 1 Hb level measurement during the 1 year prior to and after voxelotor initiation, respectively. Among the subset of patients with their Hb level tested within 30 days prior to the index date and at least 1 Hb level after index date (n=22), the baseline average Hb level was 8.0 g/dL (SD 1.4, median 7.9 g/dL, range 5.0-11.8 g/dL). Mean increase in Hb from baseline was 1.1-1.3 g/dL (Table 1) depending on the approach used to calculate Hb levels after voxelotor initiation; 55% (95% CI 32%-77%) of patients achieved a Hb increase >1 g/dL after voxelotor initiation. Among all 1275 patients, mean (SD) overall transfusion rates declined from 0.45 (1.67) PPPY pre-index to 0.31 (1.88) post-index, a change of -0.14 PPPY (P=0.005). Among 169 patients who received at least 1 transfusion in the year prior to initiation of voxelotor, the transfusion rate dropped from 3.39 (3.34) to 1.75 (4.30) PPPY, a change of -1.64 PPPY (P<0.001). Among 17 patients receiving chronic transfusions, the transfusion rate dropped from 11.29 (3.12) to 6.74 (7.37) PPPY, a change of -4.56 PPPY (P=0.013) (Table 2). After voxelotor initiation, the annualized rates of VOC were numerically reduced from 3.86 (6.69) to 3.64 (8.54) (P=0.248). To address the potential bias from the relatively short follow-up duration, similar results of transfusion and VOC rates were observed among patients with at least 30 days of follow-up or when only events within 3 months prior to index date were considered. Conclusions: Based on the first 6 months' data after the approval of voxelotor in the US, in real-world practice, voxelotor increases Hb by at least 1 g/dL, consistent with the HOPE randomized controlled trial results. Evidence suggests that transfusion rates decreased after voxelotor initiation. A favorable downward trend in VOC rates was also observed. This real-world evidence provides additional support for the use of this novel therapy in the treatment of hemolytic anemia and its associated complications in the SCD population. Further evaluation with a larger sample size and longer follow-up will help to confirm these findings. Disclosures Zaidi: Global Blood Therapeutics: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Novartis: Consultancy, Honoraria; Cyclerion: Consultancy, Honoraria; Imara: Consultancy, Honoraria; bluebird bio: Consultancy, Honoraria; Emmaus Life Sciences: Consultancy, Honoraria. Alvarez:Novartis: Membership on an entity's Board of Directors or advisory committees; Forma Therapeutics: Membership on an entity's Board of Directors or advisory committees. Lonshteyn:Policy Analysis Inc.: Current Employment; Global Blood Therapeutics: Research Funding; Novartis: Research Funding. Weycker:Policy Analysis Inc.: Current Employment, Current equity holder in publicly-traded company; Novartis: Research Funding; Global Blood Therapeutics: Research Funding. Pham:Policy Analysis Inc.: Current Employment; Global Blood Therapeutics: Research Funding; Novartis: Research Funding. Delea:Global Blood Therapeutics: Research Funding; Novartis: Research Funding; Policy Analysis Inc.: Current Employment, Current equity holder in private company. Agodoa:Global Blood Therapeutics: Current Employment, Current equity holder in publicly-traded company. Cong:Global Blood Therapeutics: Current Employment, Current equity holder in publicly-traded company. Shah:Novartis: Consultancy, Research Funding, Speakers Bureau; Global Blood Therapeutics: Consultancy, Research Funding, Speakers Bureau; CSL Behring: Consultancy; Alexion: Speakers Bureau; Bluebird Bio: Consultancy