{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,3,23]],"date-time":"2026-03-23T18:59:22Z","timestamp":1774292362520,"version":"3.50.1"},"reference-count":51,"publisher":"MDPI AG","issue":"5","license":[{"start":{"date-parts":[[2022,9,26]],"date-time":"2022-09-26T00:00:00Z","timestamp":1664150400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100000050","name":"National Heart, Lung, and Blood Institute of the National Institutes of Health","doi-asserted-by":"publisher","award":["K23HL150232"],"award-info":[{"award-number":["K23HL150232"]}],"id":[{"id":"10.13039\/100000050","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Pharmacy"],"abstract":"<jats:p>Sickle-cell disease (SCD) is an inherited hemoglobinopathy, causing lifelong complications such as painful vaso-occlusive episodes, acute chest syndrome, stroke, chronic anemia, and end-organ damage, with negative effects on quality of life and life expectancy. Within the last five years, three new treatments have been approved: L-glutamine in 2017 and crizanlizumab and voxelotor in 2019. We conducted a literature search of these three medications, and of the 31 articles meeting inclusion criteria, 6 studied L-glutamine, 9 crizanlizumab, and 16 voxelotor. Treatment with L-glutamine was associated with decrease in pain crises, hospitalizations, and time to first and second crises, with a decrease in RBC transfusion rate. Barriers to filling and taking L-glutamine included insurance denial, high deductible, and intolerability, especially abdominal pain. Crizanlizumab was associated with a reduction in pain crises and time to first crisis, with reduction in need for opioid use. Adverse effects of crizanlizumab include headache, nausea, insurance difficulty, and infusion reactions. Voxelotor was associated with increased hemoglobin and decreased markers of hemolysis. Barriers for voxelotor use included insurance denial and side effects such as headache, rash, and diarrhea. These three medications represent exciting new therapies and are generally well-tolerated though price and insurance approval remain potential barriers to access. Other studies are ongoing, particularly in the pediatric population, and more real-world studies are needed. The objective of this article is to evaluate post-approval studies of crizanlizumab, voxelotor, and L-glutamine in SCD, with a focus on real-world efficacy, side effects, and prescribing data.<\/jats:p>","DOI":"10.3390\/pharmacy10050123","type":"journal-article","created":{"date-parts":[[2022,9,28]],"date-time":"2022-09-28T03:30:37Z","timestamp":1664335837000},"page":"123","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":27,"title":["Recent Advances in Sickle-Cell Disease Therapies: A Review of Voxelotor, Crizanlizumab, and L-glutamine"],"prefix":"10.3390","volume":"10","author":[{"given":"Michael","family":"Migotsky","sequence":"first","affiliation":[{"name":"Department of Medical Education, McGaw Medical Center, Northwestern University Feinberg School of Medicine, Chicago, IL 60611, USA"},{"name":"Department of Pediatrics, Ann & Robert H. Lurie Children\u2019s Hospital of Chicago, Chicago, IL 60611, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Molly","family":"Beestrum","sequence":"additional","affiliation":[{"name":"Galter Health Sciences Library, Northwestern University Feinberg School of Medicine, Chicago, IL 60611, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4739-265X","authenticated-orcid":false,"given":"Sherif M.","family":"Badawy","sequence":"additional","affiliation":[{"name":"Division of Hematology, Oncology, and Stem Cell Transplant, Ann & Robert H. Lurie Children\u2019s Hospital of Chicago, Chicago, IL 60611, USA"},{"name":"Department of Pediatrics, Northwestern University Feinberg School of Medicine, Chicago, IL 60611, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2022,9,26]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"1561","DOI":"10.1056\/NEJMra1510865","article-title":"Sickle cell disease","volume":"376","author":"Piel","year":"2017","journal-title":"N. Engl. J. Med."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"S512","DOI":"10.1016\/j.amepre.2009.12.022","article-title":"Population estimates of sickle cell disease in the US","volume":"38","author":"Hassell","year":"2010","journal-title":"Am. J. Prev. Med."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"263","DOI":"10.1146\/annurev-pathmechdis-012418-012838","article-title":"Pathophysiology of sickle cell disease","volume":"14","author":"Sundd","year":"2019","journal-title":"Annu. Rev. Pathol. Mech. Dis."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"507","DOI":"10.1016\/j.amjmed.2008.12.020","article-title":"Complications associated with sickle cell trait: A brief narrative review","volume":"122","author":"Tsaras","year":"2009","journal-title":"Am. J. Med."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"e26369","DOI":"10.1002\/pbc.26369","article-title":"Health-related quality of life and adherence to hydroxyurea in adolescents and young adults with sickle cell disease","volume":"64","author":"Badawy","year":"2017","journal-title":"Pediatr. Blood Cancer"},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"377","DOI":"10.1002\/pbc.24176","article-title":"Health-related quality of life in sickle cell disease: Past, present, and future","volume":"59","author":"Panepinto","year":"2012","journal-title":"Pediatr. Blood Cancer"},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"e1915374","DOI":"10.1001\/jamanetworkopen.2019.15374","article-title":"Estimated life expectancy and income of patients with sickle cell disease compared with those without sickle cell disease","volume":"2","author":"Lubeck","year":"2019","journal-title":"JAMA Netw. Open"},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"1362","DOI":"10.1056\/NEJMct0708272","article-title":"Hydroxyurea for the treatment of sickle cell anemia","volume":"358","author":"Platt","year":"2008","journal-title":"N. Engl. J. Med."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"1317","DOI":"10.1056\/NEJM199505183322001","article-title":"Effect of hydroxyurea on the frequency of painful crises in sickle cell anemia","volume":"332","author":"Charache","year":"1995","journal-title":"N. Engl. J. Med."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"415","DOI":"10.1016\/j.jpeds.2009.09.044","article-title":"Adherence to hydroxyurea therapy in children with sickle cell anemia","volume":"156","author":"Thornburg","year":"2010","journal-title":"J. Pediatr."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"257","DOI":"10.1358\/dot.2020.56.4.3110575","article-title":"L-Glutamine in sickle cell disease","volume":"56","author":"Cox","year":"2020","journal-title":"Drugs Today"},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"226","DOI":"10.1056\/NEJMoa1715971","article-title":"A Phase 3 Trial of l-Glutamine in Sickle Cell Disease","volume":"379","author":"Niihara","year":"2018","journal-title":"N. Engl. J. Med."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"79","DOI":"10.1007\/s40265-019-01254-2","article-title":"Crizanlizumab: First approval","volume":"80","author":"Blair","year":"2020","journal-title":"Drugs"},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"429","DOI":"10.1056\/NEJMoa1611770","article-title":"Crizanlizumab for the Prevention of Pain Crises in Sickle Cell Disease","volume":"376","author":"Ataga","year":"2017","journal-title":"N. Engl. J. Med."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"209","DOI":"10.1007\/s40265-020-01262-7","article-title":"Voxelotor: First approval","volume":"80","author":"Blair","year":"2020","journal-title":"Drugs"},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"509","DOI":"10.1056\/NEJMoa1903212","article-title":"A Phase 3 Randomized Trial of Voxelotor in Sickle Cell Disease","volume":"381","author":"Vichinsky","year":"2019","journal-title":"N. Engl. J. Med."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"3116","DOI":"10.1182\/blood-2021-154477","article-title":"The Evaluation of Transfusion Data from the Phase 3 Clinical Study of L-Glutamine in Sickle Cell Disease","volume":"138","author":"Lam","year":"2021","journal-title":"Blood"},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"1065","DOI":"10.1182\/blood-2018-99-119720","article-title":"Consistent benefit of L-glutamine observed across patients with low, medium, and high number of crises reported in the year prior to screening-analysis from the phase 3 study of L-glutamine in sickle cell anemia","volume":"132","author":"Niihara","year":"2018","journal-title":"Blood"},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"4849","DOI":"10.1182\/blood-2019-126179","article-title":"L-Glutamine Decreases Opioid Use in Individuals with Sickle Cell Disease and Chronic Pain: A Case Series","volume":"134","author":"Wilson","year":"2019","journal-title":"Blood"},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"6","DOI":"10.1182\/blood-2020-137280","article-title":"Pediatric Patients with Sickle Cell Disease at Harbor-UCLA & Early Experience of L-Glutamine Therapy","volume":"136","author":"Gotesman","year":"2020","journal-title":"Blood"},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"2287","DOI":"10.1182\/blood-2019-126666","article-title":"Barriers to the Use of Endari\u2122 in an Urban Adult Sickle Cell Center","volume":"134","author":"Ogu","year":"2019","journal-title":"Blood"},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"2289","DOI":"10.1182\/blood-2019-125868","article-title":"Crizanlizumab Treatment Is Associated with Clinically Significant Reductions in Hospitalization in Patients with Sickle Cell Disease: Results from the Sustain Study","volume":"134","author":"Ataga","year":"2019","journal-title":"Blood"},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"55","DOI":"10.1002\/ajh.25308","article-title":"Effect of crizanlizumab on pain crises in subgroups of patients with sickle cell disease: A SUSTAIN study analysis","volume":"94","author":"Kutlar","year":"2019","journal-title":"Am. J. Hematol."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"32","DOI":"10.1182\/blood-2020-140428","article-title":"The Effect of Crizanlizumab on the Number of Days Requiring Opioid Use for Management of Pain Associated with Vaso-Occlusive Crises in Patients with Sickle Cell Disease: Results from the Sustain Trial","volume":"136","author":"Smith","year":"2020","journal-title":"Blood"},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"S335","DOI":"10.1016\/j.jval.2019.04.1637","article-title":"Pro3 successor study: Treatment and health care resource utilization by sickle cell patients who participated in the sustain study in the united states","volume":"22","author":"Shah","year":"2019","journal-title":"Value Health"},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"991","DOI":"10.1182\/blood-2019-123965","article-title":"Crizanlizumab 5.0 Mg\/Kg Exhibits a Favorable Safety Profile in Patients with Sickle Cell Disease: Pooled Data from Two Phase II Studies","volume":"134","author":"Kanter","year":"2019","journal-title":"Blood"},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"4186","DOI":"10.1182\/blood-2021-154355","article-title":"Crizanlizumab-Associated Painful Febrile Reaction in Sickle Cell Disease Patients","volume":"138","author":"Li","year":"2021","journal-title":"Blood"},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"3113","DOI":"10.1182\/blood-2021-153136","article-title":"Early Evaluation of the Use of Crizanlizumab in Sickle Cell Disease: A National Alliance of Sickle Cell Centers Study","volume":"138","author":"Kanter","year":"2021","journal-title":"Blood"},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"3112","DOI":"10.1182\/blood-2021-152362","article-title":"Rare Cases of Infusion-Related Reactions (IRRs) Presenting As Pain Events during or after Crizanlizumab Infusion in Patients (Pts) with Sickle Cell Disease (SCD): A Systematic Evaluation of Post-Marketing (PM) Reports","volume":"138","author":"Kanter","year":"2021","journal-title":"Blood"},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"1020","DOI":"10.1182\/blood-2019-130802","article-title":"Correlation of Voxelotor Exposure with Hemoglobin Response and Measures of Hemolysis in Patients from the HOPE Study","volume":"134","author":"Howard","year":"2019","journal-title":"Blood"},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"e323","DOI":"10.1016\/S2352-3026(21)00059-4","article-title":"Voxelotor in adolescents and adults with sickle cell disease (HOPE): Long-term follow-up results of an international, randomised, double-blind, placebo-controlled, phase 3 trial","volume":"8","author":"Howard","year":"2021","journal-title":"Lancet Haematol."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"E126","DOI":"10.1002\/ajh.26101","article-title":"The impact of voxelotor treatment on leg ulcers in patients with sickle cell disease","volume":"96","author":"Minniti","year":"2021","journal-title":"Am. J. Hematol."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"31","DOI":"10.1182\/blood-2020-140863","article-title":"Higher Hemoglobin Levels Achieved with Voxelotor Are Associated with Lower Vaso-occlusive Crisis Incidence: 72-Week Analysis from the HOPE Study","volume":"136","author":"Vichinsky","year":"2020","journal-title":"Blood"},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"3114","DOI":"10.1182\/blood-2021-153582","article-title":"Long-Term Safety and Efficacy of Voxelotor for Patients with Sickle Cell Disease: Results from an Open-Label Extension of the Phase 3 HOPE Trial","volume":"138","author":"Achebe","year":"2021","journal-title":"Blood"},{"key":"ref_35","first-page":"88","article-title":"Safety and efficacy of voxelotor in pediatric patients with sickle cell disease aged 4\u201311 years","volume":"5","author":"Estepp","year":"2021","journal-title":"HemaSphere"},{"key":"ref_36","first-page":"304","article-title":"Results from a phase 2a study (GBT440-007) evaluating adolescents with sickle cell disease treated with multiple doses of voxelotor (GBT440), a hbs polymerization inhibitor","volume":"2","author":"Brown","year":"2018","journal-title":"HemaSphere"},{"key":"ref_37","first-page":"S241","article-title":"Phase 2A study (GBT440-007) of voxelotor in adolescents with sickle cell disease","volume":"66","author":"Brown","year":"2019","journal-title":"Pediatr. 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Study to Evaluate the Effect of GBT440 on TCD in Pediatrics With Sickle Cell Disease (HOPE Kids 2), Available online: https:\/\/clinicaltrials.gov\/ct2\/show\/NCT04218084."}],"container-title":["Pharmacy"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2226-4787\/10\/5\/123\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T00:40:00Z","timestamp":1760143200000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2226-4787\/10\/5\/123"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2022,9,26]]},"references-count":51,"journal-issue":{"issue":"5","published-online":{"date-parts":[[2022,10]]}},"alternative-id":["pharmacy10050123"],"URL":"https:\/\/doi.org\/10.3390\/pharmacy10050123","relation":{},"ISSN":["2226-4787"],"issn-type":[{"value":"2226-4787","type":"electronic"}],"subject":[],"published":{"date-parts":[[2022,9,26]]}}}