Details

Autor(en) / Beteiligte

• Xu, Julia Z.
• Conrey, Anna
• Frey, Ingrid
• Gwaabe, Eveline
• Menapace, Laurel A.
• Tumburu, Laxminath
• Lundt, Maureen
• Lequang, Timothy
• Li, Quan
• Glass, Kristen
• Dunkelberger, Emily B.
• Iyer, Varsha
• Mangus, Heidi
• Kung, Charles
• Dang, Lenny
• Kosinski, Penelope A.
• Hawkins, Peter
• Jeffries, Neal
• Eaton, William A.
• Lay Thein, Swee

Titel

A phase 1 dose escalation study of the pyruvate kinase activator mitapivat (AG-348) in sickle cell disease

Ist Teil von

• Blood, 2022-11, Vol.140 (19), p.2053-2062

Ort / Verlag

United States: Elsevier Inc

Erscheinungsjahr

2022

Link zum Volltext

Quelle

MEDLINE

Beschreibungen/Notizen

• •We established proof of concept for activating pyruvate kinase (PK) in sickle cell disease (SCD) as a viable therapeutic approach.•Mitapivat, a PK activator, improved hematologic parameters, increased oxygen affinity, and reduced sickling in patients with SCD anemia. [Display omitted] Polymerization of deoxygenated hemoglobin S underlies the pathophysiology of sickle cell disease (SCD). In activating red blood cell pyruvate kinase and glycolysis, mitapivat (AG-348) increases adenosine triphosphate (ATP) levels and decreases the 2,3-diphosphoglycerate (2,3-DPG) concentration, an upstream precursor in glycolysis. Both changes have therapeutic potential for patients with SCD. Here, we evaluated the safety and tolerability of multiple ascending doses of mitapivat in adults with SCD with no recent blood transfusions or changes in hydroxyurea or l-glutamine therapy. Seventeen subjects were enrolled; 1 subject was withdrawn shortly after starting the study. Sixteen subjects completed 3 ascending dose levels of mitapivat (5, 20, and 50 mg, twice daily [BID]) for 2 weeks each; following a protocol amendment, the dose was escalated to 100 mg BID in 9 subjects. Mitapivat was well tolerated at all dose levels, with the most common treatment-emergent adverse events (AEs) being insomnia, headache, and hypertension. Six serious AEs (SAEs) included 4 vaso-occlusive crises (VOCs), non–VOC-related shoulder pain, and a preexisting pulmonary embolism. Two VOCs occurred during drug taper and were possibly drug related; no other SAEs were drug related. Mean hemoglobin increase at the 50 mg BID dose level was 1.2 g/dL, with 9 of 16 (56.3%) patients achieving a hemoglobin response of a ≥1 g/dL increase compared with baseline. Mean reductions in hemolytic markers and dose-dependent decreases in 2,3-DPG and increases in ATP were also observed. This study provides proof of concept that mitapivat has disease-modifying potential in patients with SCD. This trial was registered at www.clinicaltrials.gov as #NCT04000165. Xu et al report results of a phase 1 trial of mitapivat, an activator of pyruvate kinase, in 17 patients with sickle cell disease. Mitapivat decreases the concentration of 2,3-DPG, increasing hemoglobin oxygen affinity and decreasing hemoglobin S polymerization. Treatment was associated with decreases in hemolysis and increased hemoglobin in over half the patients. Further study is needed to see if it has a clinical impact on vaso-occlusive crises.