RARE DISEASE
Alpha-thalassemia
Alpha-thalassemia
Alpha-thalassemia
Drug discovery
2
drugs
With orphan designations
Overview
Alpha-thalassemia is an inherited hemoglobinopathy caused by reduced or absent alpha-globin synthesis, leading to ineffective erythropoiesis and hemolytic anemia. Severity ranges from asymptomatic carriers (1-2 mutated genes) to life-threatening hemoglobin Bart hydrops fetalis syndrome (4 mutated genes). Intermediate forms like HbH disease (3 mutations) cause chronic anemia, hepatosplenomegaly, and iron overload. Diagnosis combines hematologic indices (microcytosis/hypochromia), hemoglobin electrophoresis, and genetic testing [1][6][16].
Categories: rare genetic diseases, rare hematological diseases, rare transplant-related disorders
Research Papers
326 drug discovery papers about Alpha-thalassemia, with 3 first-in-class and 8 next-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
326 drug discovery papers about Alpha-thalassemia, with 3 first-in-class and 8 next-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
2026-07-20 | Roth Spots as the Initial Manifestation of Sickle Cell Trait with Suspected Co-inherited Alpha-Thalassemia: A Case Report
Roth spots are white-centered retinal hemorrhages representing a nonspecific morphologic endpoint of retinal capillary rupture. They have long been associated with infective endocarditis, but they are now recognized as a nonspecific sign of systemic microvascular injury. While sickle cell disease is a known cause of retinal vascular complications, their occurrence in sickle cell trait, particularly in association with co-inherited alpha-thalassemia, remains exceptionally rare. This is the case of a previously healthy 40-year-old man presented with sudden visual loss in the left eye, reduced to light perception at initial examination. Fundoscopy revealed multiple Roth spots across all quadrants, extensive macular hemorrhage, and Frisen grade 3 optic disc edema. Fluorescein angiography identified an inferior temporal branch retinal vein occlusion. An exhaustive workup excluded infectious, inflammatory, and malignant etiologies. Peripheral blood smear showed sickled erythrocytes, and hemoglobin electrophoresis demonstrated an HbS fraction of 33.6% with normal HbA2 (3.2%), a pattern consistent with sickle cell trait and suggestive of alpha-thalassemia co-inheritance.This case highlights that Roth spots may be the first ophthalmic sign of an underlying hemoglobinopathy, even in a patient with sickle cell trait. Careful systemic evaluation and multidisciplinary management are essential when white-centered retinal hemorrhages occur without an obvious cause.
2026-07-19 | [Alpha-thalassemia with Hb G-Philadelphia incidentally discovered during HbA1c testing].
Hemoglobin G-Philadelphia is an alpha-globin chain variant resulting from the substitution of asparagine by lysine at position 68 [α68(E17) Asn→Lys]. This hemoglobin (Hb) variant is generally clinically silent; however, its identification may be challenging, particularly when present in the homozygous state and co-inherited with the -α3.7 deletion. We report the case of a 28-year-old woman from southeastern Morocco presenting with refractory hypochromic microcytic anemia (Hb 10,6 g/dL, MCV 60.5 fL, MCH 20.3 pg). Owing to a family history of type 2 diabetes mellitus, HbA1c testing was performed and revealed a hemoglobin variant eluting in the D window (87.44 %) on the Bio-Rad D-100 HPLC system. Further laboratory investigations (HPLC Variant II, capillary electrophoresis, and acid pH gel electrophoresis) confirmed the presence of homozygous Hb G-Philadelphia. Molecular analysis confirmed the variant and demonstrated its association with mild α-thalassemia. Family study revealed that the daughter is a heterozygous carrier of Hb G-Philadelphia and a cis -α3.7 α-thalassemia trait.
2026-07-19 | Evaluating mitapivat for the treatment of alpha or beta thalassemia.
Thalassemia is a group of diverse genetic disorders with worldwide distribution that affects hemoglobin synthesis. Until recently, the therapeutic approach to thalassemia was symptomatic, relying on red blood cell transfusions, treatment of comorbidities and of disease-related complications. However, novel therapeutic agents have recently been developed and are gradually being integrated into routine clinical practice. One of the most promising agents is mitapivat (AG348), an oral pyruvate kinase activator that enhances the erythrocytic adenosine triphosphate (ATP) production. After series of preclinical and clinical studies, mitapivat has been suggested to be a safe and effective disease modifier for thalassemia. Large double blind randomized clinical trials have indicated that mitapivat may increase baseline hemoglobin levels, reduce transfusion burden, control ineffective erythropoiesis and hemolysis and improve quality of life. Mitapivat presents as a potential game-changer in the management of patients with both α- and β-thalassemia, regardless of transfusion dependency. However, further post-marketing evidence is required in order to evaluate mitapivat profile under real‑world conditions and routine clinical practice.
2026-06-29 | Prospective clinical validation of targeted long-read sequencing for preimplantation genetic testing of α-thalassaemia.
Preimplantation genetic testing for monogenic disorders (PGT-M) can prevent transmission of severe α-thalassaemia, but conventional workflows remain limited by family-specific assay design for direct variant detection, dependence on additional family samples for haplotype construction, and labour-intensive multi-step procedures across several platforms. Targeted long-read sequencing-based PGT-M for α-thalassaemia (tlrPGT-α-thal) integrates direct variant detection and haplotype linkage analysis within a single assay, but prospective clinical validation is lacking. This prospective clinical study enrolled 103 families at high risk of transmitting α-thalassaemia at a reproductive medicine centre between August 2024 and March 2025. All families underwent blinded parallel analysis using both conventional NGS-based PGT-M (comparator) and tlrPGT-α-thal. In the primary concordance analysis, tlrPGT-α-thal was fully concordant with conventional NGS-based PGT-M (507/507, 100.0%; exact 95% CI, 99.3-100.0). Direct variant detection was successful in 501/507 embryos (98.82%; 95% CI, 97.4-99.6), haplotype linkage was established in 505/507 embryos (99.61%; 95% CI, 98.6-100.0), and one meiotic recombination event was identified. Among 93 families proceeding to embryo transfer, 57 pregnancies underwent invasive prenatal diagnosis, and all were concordant with the corresponding tlrPGT-α-thal results. Of the 26 comparator-inconclusive embryos, tlrPGT-α-thal resolved 6 complex cases, including cases with incomplete pedigrees or insufficient informative SNPs. Among the remaining 20 embryos with HBA-region aneuploidies, genotype and parental origin could be determined in 12. The findings show that tlrPGT-α-thal enables direct detection of diverse α-thalassaemia-causing variants together with efficient haplotype linkage analysis within a single workflow, without requiring family-specific assay design or additional family samples. The method demonstrated high diagnostic accuracy while providing added value in complex scenarios. Taken together, tlrPGT-α-thal represents a simplified and broadly applicable strategy for α-thalassaemia PGT-M.
2026-06-23 | Chronic Red Cell Exchange for the Management of Alpha Thalassemia Major Complicated by Iron Overload.
Alpha thalassemia major is a severe hemoglobinopathy characterized by absent or markedly reduced alpha-globin production, necessitating lifelong blood transfusions. Chronic simple transfusions can lead to significant iron overload, often requiring iron chelation therapy. However, some patients are unable to tolerate chelation or chelation is insufficient, highlighting the need for alternative strategies for managing iron overload. This study is one of the first to evaluate the feasibility, safety, and efficacy of red blood cell exchange (RBCX) as a therapeutic option for managing iron overload while improving hemoglobin function in an alpha thalassemia major patient with iron overload despite chelation therapy. RBCX therapy was performed approximately every 3 weeks over 1 year, with frequent adjustment of exchange parameters to meet pre-transfusion target levels of functional hemoglobin. Serum ferritin levels, hemoglobin electrophoresis, and functional hemoglobin levels were tracked with each exchange transfusion. For each RBCX treatment, variant hemoglobins decreased by 3.8-fold (from 19.9% to 8.9%) and functional hemoglobin levels increased approximately 3.0 g/dL. RBCX was well tolerated and associated with a marked reduction in systemic iron burden, with serum ferritin declining 7.4-fold (86.4%) over 1 year of therapy, followed by a rise after cessation of RBCX. Cardiac iron remained within normal limits throughout the study period. In contrast, liver iron demonstrated a transient increase shortly after initiation of RBCX, but ultimately declined to levels below baseline after 1 year, even during a period in the absence of iron chelation. These findings suggest that RBCX exerts a meaningful effect on iron homeostasis and raises the possibility of a synergistic benefit when combined with iron chelation. This case highlights that RBCX is a viable therapeutic strategy to treat iron overload in patients with alpha thalassemia major.
2026-07-20 | Roth Spots as the Initial Manifestation of Sickle Cell Trait with Suspected Co-inherited Alpha-Thalassemia: A Case Report
Roth spots are white-centered retinal hemorrhages representing a nonspecific morphologic endpoint of retinal capillary rupture. They have long been associated with infective endocarditis, but they are now recognized as a nonspecific sign of systemic microvascular injury. While sickle cell disease is a known cause of retinal vascular complications, their occurrence in sickle cell trait, particularly in association with co-inherited alpha-thalassemia, remains exceptionally rare. This is the case of a previously healthy 40-year-old man presented with sudden visual loss in the left eye, reduced to light perception at initial examination. Fundoscopy revealed multiple Roth spots across all quadrants, extensive macular hemorrhage, and Frisen grade 3 optic disc edema. Fluorescein angiography identified an inferior temporal branch retinal vein occlusion. An exhaustive workup excluded infectious, inflammatory, and malignant etiologies. Peripheral blood smear showed sickled erythrocytes, and hemoglobin electrophoresis demonstrated an HbS fraction of 33.6% with normal HbA2 (3.2%), a pattern consistent with sickle cell trait and suggestive of alpha-thalassemia co-inheritance.This case highlights that Roth spots may be the first ophthalmic sign of an underlying hemoglobinopathy, even in a patient with sickle cell trait. Careful systemic evaluation and multidisciplinary management are essential when white-centered retinal hemorrhages occur without an obvious cause.
2026-07-19 | [Alpha-thalassemia with Hb G-Philadelphia incidentally discovered during HbA1c testing].
Hemoglobin G-Philadelphia is an alpha-globin chain variant resulting from the substitution of asparagine by lysine at position 68 [α68(E17) Asn→Lys]. This hemoglobin (Hb) variant is generally clinically silent; however, its identification may be challenging, particularly when present in the homozygous state and co-inherited with the -α3.7 deletion. We report the case of a 28-year-old woman from southeastern Morocco presenting with refractory hypochromic microcytic anemia (Hb 10,6 g/dL, MCV 60.5 fL, MCH 20.3 pg). Owing to a family history of type 2 diabetes mellitus, HbA1c testing was performed and revealed a hemoglobin variant eluting in the D window (87.44 %) on the Bio-Rad D-100 HPLC system. Further laboratory investigations (HPLC Variant II, capillary electrophoresis, and acid pH gel electrophoresis) confirmed the presence of homozygous Hb G-Philadelphia. Molecular analysis confirmed the variant and demonstrated its association with mild α-thalassemia. Family study revealed that the daughter is a heterozygous carrier of Hb G-Philadelphia and a cis -α3.7 α-thalassemia trait.
2026-07-19 | Evaluating mitapivat for the treatment of alpha or beta thalassemia.
Thalassemia is a group of diverse genetic disorders with worldwide distribution that affects hemoglobin synthesis. Until recently, the therapeutic approach to thalassemia was symptomatic, relying on red blood cell transfusions, treatment of comorbidities and of disease-related complications. However, novel therapeutic agents have recently been developed and are gradually being integrated into routine clinical practice. One of the most promising agents is mitapivat (AG348), an oral pyruvate kinase activator that enhances the erythrocytic adenosine triphosphate (ATP) production. After series of preclinical and clinical studies, mitapivat has been suggested to be a safe and effective disease modifier for thalassemia. Large double blind randomized clinical trials have indicated that mitapivat may increase baseline hemoglobin levels, reduce transfusion burden, control ineffective erythropoiesis and hemolysis and improve quality of life. Mitapivat presents as a potential game-changer in the management of patients with both α- and β-thalassemia, regardless of transfusion dependency. However, further post-marketing evidence is required in order to evaluate mitapivat profile under real‑world conditions and routine clinical practice.
2026-06-29 | Prospective clinical validation of targeted long-read sequencing for preimplantation genetic testing of α-thalassaemia.
Preimplantation genetic testing for monogenic disorders (PGT-M) can prevent transmission of severe α-thalassaemia, but conventional workflows remain limited by family-specific assay design for direct variant detection, dependence on additional family samples for haplotype construction, and labour-intensive multi-step procedures across several platforms. Targeted long-read sequencing-based PGT-M for α-thalassaemia (tlrPGT-α-thal) integrates direct variant detection and haplotype linkage analysis within a single assay, but prospective clinical validation is lacking. This prospective clinical study enrolled 103 families at high risk of transmitting α-thalassaemia at a reproductive medicine centre between August 2024 and March 2025. All families underwent blinded parallel analysis using both conventional NGS-based PGT-M (comparator) and tlrPGT-α-thal. In the primary concordance analysis, tlrPGT-α-thal was fully concordant with conventional NGS-based PGT-M (507/507, 100.0%; exact 95% CI, 99.3-100.0). Direct variant detection was successful in 501/507 embryos (98.82%; 95% CI, 97.4-99.6), haplotype linkage was established in 505/507 embryos (99.61%; 95% CI, 98.6-100.0), and one meiotic recombination event was identified. Among 93 families proceeding to embryo transfer, 57 pregnancies underwent invasive prenatal diagnosis, and all were concordant with the corresponding tlrPGT-α-thal results. Of the 26 comparator-inconclusive embryos, tlrPGT-α-thal resolved 6 complex cases, including cases with incomplete pedigrees or insufficient informative SNPs. Among the remaining 20 embryos with HBA-region aneuploidies, genotype and parental origin could be determined in 12. The findings show that tlrPGT-α-thal enables direct detection of diverse α-thalassaemia-causing variants together with efficient haplotype linkage analysis within a single workflow, without requiring family-specific assay design or additional family samples. The method demonstrated high diagnostic accuracy while providing added value in complex scenarios. Taken together, tlrPGT-α-thal represents a simplified and broadly applicable strategy for α-thalassaemia PGT-M.
2026-06-23 | Chronic Red Cell Exchange for the Management of Alpha Thalassemia Major Complicated by Iron Overload.
Alpha thalassemia major is a severe hemoglobinopathy characterized by absent or markedly reduced alpha-globin production, necessitating lifelong blood transfusions. Chronic simple transfusions can lead to significant iron overload, often requiring iron chelation therapy. However, some patients are unable to tolerate chelation or chelation is insufficient, highlighting the need for alternative strategies for managing iron overload. This study is one of the first to evaluate the feasibility, safety, and efficacy of red blood cell exchange (RBCX) as a therapeutic option for managing iron overload while improving hemoglobin function in an alpha thalassemia major patient with iron overload despite chelation therapy. RBCX therapy was performed approximately every 3 weeks over 1 year, with frequent adjustment of exchange parameters to meet pre-transfusion target levels of functional hemoglobin. Serum ferritin levels, hemoglobin electrophoresis, and functional hemoglobin levels were tracked with each exchange transfusion. For each RBCX treatment, variant hemoglobins decreased by 3.8-fold (from 19.9% to 8.9%) and functional hemoglobin levels increased approximately 3.0 g/dL. RBCX was well tolerated and associated with a marked reduction in systemic iron burden, with serum ferritin declining 7.4-fold (86.4%) over 1 year of therapy, followed by a rise after cessation of RBCX. Cardiac iron remained within normal limits throughout the study period. In contrast, liver iron demonstrated a transient increase shortly after initiation of RBCX, but ultimately declined to levels below baseline after 1 year, even during a period in the absence of iron chelation. These findings suggest that RBCX exerts a meaningful effect on iron homeostasis and raises the possibility of a synergistic benefit when combined with iron chelation. This case highlights that RBCX is a viable therapeutic strategy to treat iron overload in patients with alpha thalassemia major.
Access all drug discovery papers and probability of success in trials forecasts:
Access all drug discovery papers and probability of success in trials forecasts:
Drug Discovery Landscape
2 orphan drug designations for Alpha-thalassemia, including 1 approved therapy.
2 orphan drug designations for Alpha-thalassemia, including 1 approved therapy.
Drug | Therapy type | Regulator | Orphan designation | Approval | Sponsor |
|---|---|---|---|---|---|
luspatercept | proteins | FDA | 2021-09-21 | — | Celgene Corporation |
deferasirox [Exjade; Jadenu Sprinkles] | small molecules | FDA | 2015-02-24 | 2013-01-23 | Novartis Pharmaceuticals Corporation |
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