PMID- 35576529
OWN - NLM
STAT- MEDLINE
DCOM- 20221114
LR  - 20231111
IS  - 1528-0020 (Electronic)
IS  - 0006-4971 (Print)
IS  - 0006-4971 (Linking)
VI  - 140
IP  - 19
DP  - 2022 Nov 10
TI  - A phase 1 dose escalation study of the pyruvate kinase activator mitapivat 
      (AG-348) in sickle cell disease.
PG  - 2053-2062
LID - 10.1182/blood.2022015403 [doi]
AB  - 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      1 subject was withdrawn shortly after starting the study.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.
FAU - Xu, Julia Z
AU  - Xu JZ
AUID- ORCID: 0000-0003-4147-8388
AD  - Sickle Cell Branch, National Heart, Lung, and Blood Institute, National 
      Institutes of Health, Bethesda, MD.
FAU - Conrey, Anna
AU  - Conrey A
AD  - Sickle Cell Branch, National Heart, Lung, and Blood Institute, National 
      Institutes of Health, Bethesda, MD.
FAU - Frey, Ingrid
AU  - Frey I
AD  - Sickle Cell Branch, National Heart, Lung, and Blood Institute, National 
      Institutes of Health, Bethesda, MD.
FAU - Gwaabe, Eveline
AU  - Gwaabe E
AD  - Sickle Cell Branch, National Heart, Lung, and Blood Institute, National 
      Institutes of Health, Bethesda, MD.
FAU - Menapace, Laurel A
AU  - Menapace LA
AD  - Sickle Cell Branch, National Heart, Lung, and Blood Institute, National 
      Institutes of Health, Bethesda, MD.
FAU - Tumburu, Laxminath
AU  - Tumburu L
AUID- ORCID: 0000-0002-7548-0243
AD  - Sickle Cell Branch, National Heart, Lung, and Blood Institute, National 
      Institutes of Health, Bethesda, MD.
FAU - Lundt, Maureen
AU  - Lundt M
AD  - Sickle Cell Branch, National Heart, Lung, and Blood Institute, National 
      Institutes of Health, Bethesda, MD.
FAU - Lequang, Timothy
AU  - Lequang T
AD  - Sickle Cell Branch, National Heart, Lung, and Blood Institute, National 
      Institutes of Health, Bethesda, MD.
FAU - Li, Quan
AU  - Li Q
AD  - Laboratory of Chemical Physics, National Institute of Diabetes and Digestive and 
      Kidney Diseases, National Institutes of Health, Bethesda, MD.
FAU - Glass, Kristen
AU  - Glass K
AD  - Laboratory of Chemical Physics, National Institute of Diabetes and Digestive and 
      Kidney Diseases, National Institutes of Health, Bethesda, MD.
FAU - Dunkelberger, Emily B
AU  - Dunkelberger EB
AD  - Laboratory of Chemical Physics, National Institute of Diabetes and Digestive and 
      Kidney Diseases, National Institutes of Health, Bethesda, MD.
FAU - Iyer, Varsha
AU  - Iyer V
AD  - Agios Pharmaceuticals, Inc., Cambridge, MA.
FAU - Mangus, Heidi
AU  - Mangus H
AD  - Agios Pharmaceuticals, Inc., Cambridge, MA.
FAU - Kung, Charles
AU  - Kung C
AD  - Agios Pharmaceuticals, Inc., Cambridge, MA.
FAU - Dang, Lenny
AU  - Dang L
AUID- ORCID: 0000-0002-2073-6109
AD  - Agios Pharmaceuticals, Inc., Cambridge, MA.
FAU - Kosinski, Penelope A
AU  - Kosinski PA
AUID- ORCID: 0000-0002-4465-0924
AD  - Agios Pharmaceuticals, Inc., Cambridge, MA.
FAU - Hawkins, Peter
AU  - Hawkins P
AD  - Agios Pharmaceuticals, Inc., Cambridge, MA.
FAU - Jeffries, Neal
AU  - Jeffries N
AD  - Office of Biostatistics Research, National Heart, Lung, and Blood Institute, 
      National Institutes of Health, Bethesda, MD.
FAU - Eaton, William A
AU  - Eaton WA
AUID- ORCID: 0000-0002-9244-5407
AD  - Laboratory of Chemical Physics, National Institute of Diabetes and Digestive and 
      Kidney Diseases, National Institutes of Health, Bethesda, MD.
FAU - Lay Thein, Swee
AU  - Lay Thein S
AUID- ORCID: 0000-0002-9835-6501
AD  - Sickle Cell Branch, National Heart, Lung, and Blood Institute, National 
      Institutes of Health, Bethesda, MD.
LA  - eng
SI  - ClinicalTrials.gov/NCT04000165
PT  - Clinical Trial, Phase I
PT  - Journal Article
PL  - United States
TA  - Blood
JT  - Blood
JID - 7603509
RN  - 2WTV10SIKH (mitapivat)
RN  - EC 2.7.1.40 (Pyruvate Kinase)
RN  - 8558G7RUTR (Pyruvic Acid)
RN  - 138-81-8 (2,3-Diphosphoglycerate)
RN  - 0 (Hemoglobins)
RN  - 8L70Q75FXE (Adenosine Triphosphate)
SB  - IM
CIN - Blood. 2022 Nov 10;140(19):2005-2006. PMID: 36355466
MH  - Adult
MH  - Humans
MH  - *Pyruvate Kinase
MH  - Pyruvic Acid
MH  - 2,3-Diphosphoglycerate
MH  - *Anemia, Sickle Cell/drug therapy
MH  - Hemoglobins
MH  - Adenosine Triphosphate
PMC - PMC9837441
COIS- Conflict-of-interest disclosure: V.I., H.M., C.K., L.D., P.A.K., and P.H. are 
      employed by and are stockholders in Agios. H.M. and P.H. are stockholders in 
      Bristol-Myers Squibb. V.I. is a stockholder in Novartis. The remaining authors 
      declare no competing financial interests.
EDAT- 2022/05/17 06:00
MHDA- 2022/11/15 06:00
PMCR- 2023/11/10
CRDT- 2022/05/16 16:13
PHST- 2022/05/11 00:00 [accepted]
PHST- 2022/01/05 00:00 [received]
PHST- 2022/05/17 06:00 [pubmed]
PHST- 2022/11/15 06:00 [medline]
PHST- 2022/05/16 16:13 [entrez]
PHST- 2023/11/10 00:00 [pmc-release]
AID - S0006-4971(22)00663-2 [pii]
AID - 10.1182/blood.2022015403 [doi]
PST - ppublish
SO  - Blood. 2022 Nov 10;140(19):2053-2062. doi: 10.1182/blood.2022015403.