PMID- 37934880
OWN - NLM
STAT- MEDLINE
DCOM- 20240108
LR  - 20240110
IS  - 2473-9537 (Electronic)
IS  - 2473-9529 (Print)
IS  - 2473-9529 (Linking)
VI  - 7
IP  - 24
DP  - 2023 Dec 26
TI  - One-year safety and efficacy of mitapivat in sickle cell disease: follow-up 
      results of a phase 2, open-label study.
PG  - 7539-7550
LID - 10.1182/bloodadvances.2023011477 [doi]
AB  - Targeting the primary pathogenic event of sickle cell disease (SCD), the 
      polymerization of sickle hemoglobin (HbS), may prevent downstream clinical 
      events. Mitapivat, an oral pyruvate kinase (PK) activator, has therapeutic 
      potential by increasing adenosine triphosphate (ATP) and decreasing 
      2,3-diphosphoglycerate (2,3-DPG), a glycolytic red blood cell (RBC) intermediate. 
      In the previously reported 8-week dose-finding period of this phase 2, 
      investigator-initiated, open-label study, mitapivat was well tolerated and showed 
      efficacy in SCD. Here, the 1-year fixed-dose extension period is reported in 
      which 9 of 10 included patients (90%) aged >/=16 years with SCD (HbSS, HbS/beta0, or 
      HbS/beta+) continued with mitapivat. Mostly mild treatment-emergent adverse events 
      (AEs) (most commonly, transaminase increase and headache) were still reported. 
      Apart from the reported nontreatment-related serious AE (SAE) of a urinary tract 
      infection in the dose-finding period, 1 nontreatment-related SAE occurred in the 
      fixed-dose extension period in a patient who died of massive pulmonary embolism 
      due to COVID-19. Importantly, sustained improvement in Hb level (mean increase, 
      1.1 +/- 0.7 g/dL; P = .0014) was seen, which was accompanied by decreases in 
      markers of hemolysis. In addition, the annualized rate of vaso-occlusive events 
      reduced significantly from a historic baseline of 1.33 +/- 1.32 to 0.64 +/- 0.87 (P = 
      .0489) when combining the dose-finding period and fixed-dose extension period. 
      Cellularly, the ATP:2,3-DPG ratio and Hb-oxygen affinity significantly increased 
      and RBC sickling (point of sickling) nonsignificantly reduced. Overall, this 
      study demonstrated 1-year safety and efficacy of treatment with mitapivat in SCD, 
      supporting further evaluation in ongoing phase 2/3 study (RISE UP, NCT05031780). 
      This trial was registered at https://www.clinicaltrialsregister.eu/ as NL8517 and 
      EudraCT 2019-003438-18.
CI  - (c) 2023 by The American Society of Hematology. Licensed under Creative Commons 
      Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0), 
      permitting only noncommercial, nonderivative use with attribution. All other 
      rights reserved.
FAU - van Dijk, Myrthe J
AU  - van Dijk MJ
AD  - Center for Benign Hematology, Thrombosis and Hemostasis - Van Creveldkliniek, 
      University Medical Center Utrecht, Utrecht University, Utrecht, The Netherlands.
AD  - Department of Central Diagnostic Laboratory - Research, University Medical Center 
      Utrecht, Utrecht University, Utrecht, The Netherlands.
FAU - Rab, Minke A E
AU  - Rab MAE
AUID- ORCID: 0000-0002-8306-8726
AD  - Department of Central Diagnostic Laboratory - Research, University Medical Center 
      Utrecht, Utrecht University, Utrecht, The Netherlands.
AD  - Department of Hematology, Erasmus MC, University Medical Center Rotterdam, 
      Rotterdam, The Netherlands.
FAU - van Oirschot, Brigitte A
AU  - van Oirschot BA
AD  - Department of Central Diagnostic Laboratory - Research, University Medical Center 
      Utrecht, Utrecht University, Utrecht, The Netherlands.
FAU - Bos, Jennifer
AU  - Bos J
AD  - Department of Central Diagnostic Laboratory - Research, University Medical Center 
      Utrecht, Utrecht University, Utrecht, The Netherlands.
FAU - Derichs, Cleo
AU  - Derichs C
AD  - Center for Benign Hematology, Thrombosis and Hemostasis - Van Creveldkliniek, 
      University Medical Center Utrecht, Utrecht University, Utrecht, The Netherlands.
FAU - Rijneveld, Anita W
AU  - Rijneveld AW
AD  - Department of Hematology, Erasmus MC, University Medical Center Rotterdam, 
      Rotterdam, The Netherlands.
FAU - Cnossen, Marjon H
AU  - Cnossen MH
AUID- ORCID: 0000-0003-1557-2995
AD  - Department of Pediatric Hematology, Erasmus MC Sophia Children's Hospital, 
      University Medical Center Rotterdam, Rotterdam, The Netherlands.
FAU - Nur, Erfan
AU  - Nur E
AUID- ORCID: 0000-0002-7069-930X
AD  - Department of Hematology, Amsterdam University Medical Center, University of 
      Amsterdam, Amsterdam, The Netherlands.
AD  - Department of Blood Cell Research, Sanquin Research, Amsterdam, The Netherlands.
FAU - Biemond, Bart J
AU  - Biemond BJ
AUID- ORCID: 0000-0002-4426-5743
AD  - Department of Hematology, Amsterdam University Medical Center, University of 
      Amsterdam, Amsterdam, The Netherlands.
FAU - Bartels, Marije
AU  - Bartels M
AUID- ORCID: 0000-0001-9685-1755
AD  - Center for Benign Hematology, Thrombosis and Hemostasis - Van Creveldkliniek, 
      University Medical Center Utrecht, Utrecht University, Utrecht, The Netherlands.
FAU - Jans, Judith J M
AU  - Jans JJM
AD  - Section Metabolic Diagnostics, Department of Genetics, University Medical Center 
      Utrecht, Utrecht University, Utrecht, The Netherlands.
FAU - van Solinge, Wouter W
AU  - van Solinge WW
AD  - Department of Central Diagnostic Laboratory - Research, University Medical Center 
      Utrecht, Utrecht University, Utrecht, The Netherlands.
FAU - Schutgens, Roger E G
AU  - Schutgens REG
AUID- ORCID: 0000-0002-2762-6033
AD  - Center for Benign Hematology, Thrombosis and Hemostasis - Van Creveldkliniek, 
      University Medical Center Utrecht, Utrecht University, Utrecht, The Netherlands.
FAU - van Wijk, Richard
AU  - van Wijk R
AD  - Department of Central Diagnostic Laboratory - Research, University Medical Center 
      Utrecht, Utrecht University, Utrecht, The Netherlands.
FAU - van Beers, Eduard J
AU  - van Beers EJ
AUID- ORCID: 0000-0002-3934-7189
AD  - Center for Benign Hematology, Thrombosis and Hemostasis - Van Creveldkliniek, 
      University Medical Center Utrecht, Utrecht University, Utrecht, The Netherlands.
LA  - eng
SI  - ClinicalTrials.gov/NCT05031780
PT  - Clinical Trial, Phase II
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
PL  - United States
TA  - Blood Adv
JT  - Blood advances
JID - 101698425
RN  - 138-81-8 (2,3-Diphosphoglycerate)
RN  - 8L70Q75FXE (Adenosine Triphosphate)
RN  - 0 (Hemoglobin, Sickle)
RN  - 2WTV10SIKH (mitapivat)
SB  - IM
MH  - Humans
MH  - 2,3-Diphosphoglycerate
MH  - Adenosine Triphosphate
MH  - *Anemia, Sickle Cell/complications
MH  - Follow-Up Studies
MH  - Hemoglobin, Sickle
MH  - Adolescent
MH  - Adult
PMC - PMC10761354
COIS- Conflict-of-interest disclosure: M.A.E.R. and R.v.W. receive research funding 
      from Axcella Therapeutics and Pfizer. M.A.E.R., R.v.W., and E.J.v.B. receive 
      research funding from and are consultants for Agios Pharmaceuticals Inc. R.v.W. 
      and E.J.v.B. are consultants for Pfizer. M.H.C. (institution) has received 
      investigator-initiated research and travel grants as well as speaker fees over 
      the years from the Netherlands Organisation for Scientific Research and 
      Netherlands National Research Agenda, the Netherlands Organization for Health 
      Research and Development (ZonMw), the Dutch Innovatiefonds Zorgverzekeraars, 
      Stichting Haemophilia, Baxter/Baxalta/Shire/Takeda, Pfizer, Bayer Schering 
      Pharma, CSL Behring, Sobi Biogen, Novo Nordisk, Novartis, Roche, and Nordic 
      Pharma,; and has served as a steering board member for Roche, Bayer, and 
      Novartis. E.N. receives research funding from Novartis and Emmaus and 
      participates in advisory board of Novartis. B.J.B. receives research funding from 
      Sanquin, Pfizer, and Novartis; and has participated in the advisory boards of 
      Novartis, Global Blood Therapeutics /Pfizer, Novo Nordisk, Celgene, Chiesi, CSL 
      Behring, and bluebird bio. R.E.G.S. has received research funding and/or speaker 
      fees from Bayer, CSL Behring, Hemab, NovoNordisk, Octapharma, Sanofi, and Sobi 
      (all paid to institution). The remaining authors declare no competing financial 
      interests.
EDAT- 2023/11/07 18:42
MHDA- 2023/12/17 13:19
PMCR- 2023/11/10
CRDT- 2023/11/07 15:13
PHST- 2023/10/12 00:00 [accepted]
PHST- 2023/08/18 00:00 [received]
PHST- 2023/12/17 13:19 [medline]
PHST- 2023/11/07 18:42 [pubmed]
PHST- 2023/11/07 15:13 [entrez]
PHST- 2023/11/10 00:00 [pmc-release]
AID - 498652 [pii]
AID - 10.1182/bloodadvances.2023011477 [doi]
PST - ppublish
SO  - Blood Adv. 2023 Dec 26;7(24):7539-7550. doi: 10.1182/bloodadvances.2023011477.