AG-348 enhances pyruvate kinase activity in red blood cells from patients with pyruvate kinase deficiency

Kung, Charles; Hixon, Jeff; Kosinski, Penelope A.; Cianchetta, Giovanni; Histen, Gavin; Chen, Yue; Hill, Colin; Größ, Stefan; Si, Yaguang; Johnson, Kendall; DeLaBarre, Byron; Luo, Zhiyong; Z, Gu; Yao, Gui Lan; Tang, Huachun; Fang, Cheng; Xu, Yuan; Lv, Xiaobing; Biller, Scott A.; Su, Shinsan M.; Yang, Hua; Popovici‐Muller, Janeta; Salituro, Francesco G.; Silverman, Lee; Dang, Lenny

doi:10.1182/blood-2016-11-753525

Cited by 87 publications

(83 citation statements)

References 35 publications

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“…[2][3][4][5] In preclinical studies, AG-348 activated the majority of the mutant PK-R enzymes assessed as well as wild-type PK-R. 5 These healthy volunteer studies therefore support the hypothesis that AG-348 could be an effective treatment for PK deficiency. The decrease in 2,3-DPG and increase in ATP blood levels reached 90% of maximal response between AG-348 dose levels that were well tolerated (120 and 360 mg every 12 hours).…”

Section: Discussionmentioning

confidence: 83%

“…16 Current treatments are supportive only and include exchange transfusions and phototherapy for newborns and blood transfusions, splenectomy, and cholecystectomy as needed in children and adults. 5 In blood samples from PK-R-deficient patients, ex vivo treatment with AG-348 increased PK-R activity (by 1.3-to 3.4-fold) and induced metabolic changes that include increased levels of ATP (by 1.3-to 2.4-fold), which is consistent with increased glycolytic pathway activity. The chemical structure of AG-348 is shown in Supplemental Figure S1.…”

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confidence: 78%

“…[2][3][4][5] It is hypothesized that the deficiency of ATP impairs the These 2 phase 1 randomized, placebo-controlled, double-blind healthy-volunteer studies assessed the safety, tolerability, and pharmacokinetics/pharmacodynamics of AG-348, a first-in-class allosteric PK-R activator.…”

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confidence: 99%

“…[2][3][4][5] It is hypothesized that the deficiency of ATP impairs the More than 250 mutations (most commonly missense) that result in functional deficiency of the R isoform of PK-R have been identified.…”

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confidence: 99%

“…15,17 AG-348 is a novel, first-in-class, orally bioavailable, small-molecule allosteric activator of PK-R. 5 Mice with wild-type PK-R treated with AG-348 had increased PK-R activity levels, as well as increased ATP and decreased 2,3-DPG levels, which is consistent with in vivo activation of PK-R. 5 Together, these data support the hypothesis that AG-348 directly targets the metabolic defect underlying PK deficiency and may have the potential to be an effective disease-altering treatment for PK deficiency. In biochemical studies using recombinantly expressed proteins, AG-348 increased the activity of both wild-type PK-R and a spectrum of mutant PK-R enzymes by 2-to 6-fold.…”

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confidence: 99%

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Phase 1 Single‐ and Multiple‐Ascending‐Dose Randomized Studies of the Safety, Pharmacokinetics, and Pharmacodynamics of AG‐348, a First‐in‐Class Allosteric Activator of Pyruvate Kinase R, in Healthy Volunteers

Yang

Merica

Chen

et al. 2018

Clinical Pharm in Drug Dev

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Pyruvate kinase deficiency is a chronic hemolytic anemia caused by mutations in PK-R, a key glycolytic enzyme in erythrocytes. These 2 phase 1 randomized, placebo-controlled, double-blind healthy-volunteer studies assessed the safety, tolerability, and pharmacokinetics/pharmacodynamics of AG-348, a first-in-class allosteric PK-R activator. Twelve sequential cohorts were randomized 2:6 to receive oral placebo or AG-348, respectively, as a single dose (30-2500 mg) in the single-ascending-dose (SAD) study (ClinicalTrials.gov: NCT02108106) or 15-700 mg every 12 hours or 120 mg every 24 hours, for 14 days in the multiple-ascending-dose (MAD) study (ClinicalTrials.gov: NCT02149966). All 48 subjects completed the fasted SAD part; 44 of 48 completed the MAD (2 discontinued because of adverse events [AEs], 2 withdrew consent). The most common treatment-related AEs in AG-348-treated subjects were headache (16.7% [SAD] and 13.9% [MAD]) and nausea (13.9%, both studies). AE frequency increased at AG-348 doses ≥ 700 mg (SAD) and at 700 mg every 12 hours (MAD); 1 grade ≥ 3 AE occurred in the latter cohort. Pharmacokinetics were favorable with low variability. Dose-dependent changes in blood glycolytic intermediates consistent with glycolytic pathway activation were observed at all MAD doses, supporting future trials investigating the potential of AG-348 for treating PK deficiency or other anemias.

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Section: Discussionmentioning

confidence: 83%

mentioning

confidence: 78%

mentioning

confidence: 99%

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confidence: 99%

mentioning

confidence: 99%

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Phase 1 Single‐ and Multiple‐Ascending‐Dose Randomized Studies of the Safety, Pharmacokinetics, and Pharmacodynamics of AG‐348, a First‐in‐Class Allosteric Activator of Pyruvate Kinase R, in Healthy Volunteers

Yang

Merica

Chen

et al. 2018

Clinical Pharm in Drug Dev

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Red cell disorders: anaemia, jaundice, polycythaemia and cyanosis

2022

Neonatal Haematology

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Multi‐gene panel testing improves diagnosis and management of patients with hereditary anemias

et al. 2018

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Mutations in more than 70 genes cause hereditary anemias (HA), a highly heterogeneous group of rare/low frequency disorders in which we included: hyporegenerative anemias, as congenital dyserythropoietic anemia (CDA) and Diamond-Blackfan anemia; hemolytic anemias due to erythrocyte membrane defects, as hereditary spherocytosis and stomatocytosis; hemolytic anemias due to enzymatic defects. The study describes the diagnostic workflow for HA, based on the development of two consecutive versions of a targeted-NGS panel, including 34 and 71 genes, respectively. Seventy-four probands from 62 unrelated families were investigated. Our study includes the most comprehensive gene set for these anemias and the largest cohort of patients described so far. We obtained an overall diagnostic yield of 64.9%. Despite 54.2% of cases showed conclusive diagnosis fitting well to the clinical suspicion, the multi-gene analysis modified the original clinical diagnosis in 45.8% of patients (nonmatched phenotype-genotype). Of note, 81.8% of nonmatched patients were clinically suspected to suffer from CDA. Particularly, 45.5% of the probands originally classified as CDA exhibited a conclusive diagnosis of chronic anemia due to enzymatic defects, mainly due to mutations in PKLR gene. Interestingly, we also identified a syndromic CDA patient with mild anemia and epilepsy, showing a homozygous mutation in CAD gene, recently associated to early infantile epileptic encephalopathy-50 and CDA-like anemia. Finally, we described a patient showing marked iron overload due to the coinheritance of PIEZO1 and SEC23B mutations, demonstrating that the multi-gene approach is valuable not only for achieving a correct and definitive diagnosis, but also for guiding treatment.

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AG-348 enhances pyruvate kinase activity in red blood cells from patients with pyruvate kinase deficiency

Abstract: Key Points AG-348 is a small-molecule allosteric activator of WT red cell pyruvate kinase as well as mutant enzymes associated with hemolytic anemia. Activity in vitro, in mice, and in red blood cells suggests it may address the underlying molecular pathology in PK deficiency patients.

Cited by 87 publications

References 35 publications

Phase 1 Single‐ and Multiple‐Ascending‐Dose Randomized Studies of the Safety, Pharmacokinetics, and Pharmacodynamics of AG‐348, a First‐in‐Class Allosteric Activator of Pyruvate Kinase R, in Healthy Volunteers

Phase 1 Single‐ and Multiple‐Ascending‐Dose Randomized Studies of the Safety, Pharmacokinetics, and Pharmacodynamics of AG‐348, a First‐in‐Class Allosteric Activator of Pyruvate Kinase R, in Healthy Volunteers

Red cell disorders: anaemia, jaundice, polycythaemia and cyanosis

Multi‐gene panel testing improves diagnosis and management of patients with hereditary anemias

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