Thalassemia is an inherited red blood cell disorder whereby the qualitative and/or quantitative imbalance in α- to β-globin ratio results in hemolysis and ineffective erythropoiesis. Oxidative stress, from the precipitated excess globin and free iron, is a major factor that drives hemolysis and ineffective erythropoiesis. Pyruvate kinase activity and adenosine triphosphate availability are reduced due to the overwhelmed cellular antioxidant system from the excessive oxidative stress. Mitapivat, a pyruvate kinase activator in development as a treatment for thalassemia, was shown to increase hemoglobin and reduce hemolysis in a small phase 2 single-arm trial of patients with α- and β-thalassemia. The ongoing phase 3 studies with mitapivat and the phase 2 study with etavopivat will examine the role of pyruvate kinase activators as disease modifying agents in thalassemia.

1.
Taher
AT
,
Musallam
KM
,
Cappellini
MD
.
β-Thalassemias
.
N Engl J Med
.
2021
;
384
(
8
):
727
-
743
.
doi:10.1056/NEJMra2021838
.
2.
Musallam
KM
,
Cappellini
MD
,
Taher
AT
.
Variations in hemoglobin level and morbidity burden in non-transfusion-dependent β-thalassemia
.
Ann Hematol
.
2021
;
100
(
7
):
1903
-
1905
.
doi:10.1007/s00277-021-04456-5
.
3.
Cappellini
MD
,
Viprakasit
V
,
Taher
AT
, et al
;
BELIEVE Investigators
.
A phase 3 trial of luspatercept in patients with transfusion-dependent β-thalassemia
.
N Engl J Med
.
2020
;
382
(
13
):
1219
-
1231
.
doi:10.1056/NEJMoa1910182
.
4.
van Dijk
MJ
,
de Wilde
JRA
,
Bartels
M
, et al.
Activation of pyruvate kinase as therapeutic option for rare hemolytic anemias: shedding new light on an old enzyme
.
Blood Rev
.
2023
;
61
(
13
):
101103
.
doi:10.1016/j.blre.2023.101103
.
5.
Mettananda
S
,
Gibbons
RJ
,
Higgs
DR
.
α-Globin as a molecular target in the treatment of β-thalassemia
.
Blood
.
2015
;
125
(
24
):
3694
-
3701
.
doi:10.1182/blood-2015-03-633594
.
6.
Guillem
F
,
Dussiot
M
,
Colin
E
, et al.
XPO1 regulates erythroid differentiation and is a new target for the treatment of β-thalassemia
.
Haematologica
.
2020
;
105
(
9
):
2240
-
2249
.
doi:10.3324/haematol.2018.210054
.
7.
Longo
F
,
Piolatto
A
,
Ferrero
GB
,
Piga
A.
Ineffective erythropoiesis in β-thalassaemia: key steps and therapeutic options by drugs
.
Int J Mol Sci
.
2021
;
22
(
13
).
doi:10.3390/ijms22137229
.
8.
Fucharoen
S
,
Viprakasit
V.
Hb H disease: clinical course and disease modifiers
.
Hematology Am Soc Hematol Educ Program
.
2009
;
2009
(
1
):
26
34
.
doi:10.1182/asheducation-2009.1.26
.
9.
Srinoun
K
,
Sathirapongsasuti
N
,
Paiboonsukwong
K
,
Sretrirutchai
S
,
Wongchanchailert
M
,
Fucharoen
S.
miR-144 regulates oxidative stress tolerance of thalassemic erythroid cell via targeting NRF2
.
Ann Hematol
.
2019
;
98
(
9
):
2045
-
2052
.
doi:10.1007/s00277-019-03737-4
.
10.
Yao
X
,
Xu
L-H
,
Xu
H-G
,
Li
X-Y
,
Liu
Y
,
Fang
J-P
.
Iron metabolism and oxidative status in patients with Hb H disease
.
Hemoglobin
.
2019
;
43
(
1
):
38
-
41
.
doi:10.1080/03630269.2019.1575850
.
11.
Putburee
R
,
Jetsrisuparb
A
,
Fucharoen
S
,
Tripatara
A.
Mitochondrial ferritin expression in erythroid cells from patients with alpha-thalassaemia
.
Hematology
.
2018
;
23
(
10
):
844
-
848
.
doi:10.1080/10245332.2018.1496812
.
12.
Ting
YL
,
Naccarato
S
,
Qualtieri
A
,
Chidichimo
G
,
Brancati
C.
In vivo metabolic studies of glucose, ATP and 2,3-DPG in beta-thalassaemia intermedia, heterozygous beta-thalassaemic and normal erythrocytes: 13C and 31P MRS studies
.
Br J Haematol
.
1994
;
88
(
3
):
547
-
554
.
doi:10.1111/j.1365-2141.1994.tb05072.x
.
13.
Chakraborty
I
,
Mishra
R
,
Gachhui
R
,
Kar
M.
Distortion of β-globin chain of hemoglobin alters the pathway of erythrocytic glucose metabolism through band 3 protein
.
Arch Med Res
.
2012
;
43
(
2
):
112
-
116
.
doi:10.1016/j.arcmed.2012.02.003
.
14.
Rab
MAE
,
van Oirschot
BA
,
van Straaten
S
, et al.
Decreased activity and stability of pyruvate kinase in hereditary hemolytic anemia: a potential target for therapy by AG-348 (Mitapivat), an allosteric activator of red blood cell pyruvate kinase
.
Blood
.
2019
;
134
(
suppl 1
):
3506
.
doi:10.1182/blood-2019-129996
.
15.
Matte
A
,
Federti
E
,
Kung
C
, et al.
The pyruvate kinase activator mitapivat reduces hemolysis and improves anemia in a β-thalassemia mouse model
.
J Clin Invest
.
2021
;
131
(
10
).
doi:10.1172/JCI144206
.
16.
Mattè
A
,
Kosinski
PA
,
Federti
E
, et al.
Mitapivat, a pyruvate kinase activator, improves transfusion burden and reduces iron overload in β-thalassemic mice
.
Haematologica
.
2023
.
doi:10.3324/haematol.2022.282614
(Epub ahead of print).
17.
Taher
A
,
Vichinsky
E
,
Musallam
K
,
Cappellini
MD
,
Viprakasit
V.
Guidelines for the Management of Non Transfusion Dependent Thalassaemia (NTDT) [Internet]
.
Weatherall
D
, ed.
Nicosia (Cyprus)
:
Thalassaemia International Federation
;
2013
.
18.
Kuo
KHM
,
Layton
DM
,
Lal
A
, et al.
Safety and efficacy of mitapivat, an oral pyruvate kinase activator, in adults with non-transfusion dependent α-thalassaemia or β-thalassaemia: an open-label, multicentre, phase 2 study
.
Lancet
.
2022
;
400
(
10351
):
493
-
501
.
doi:10.1016/S0140-6736(22)01337-X
.
19.
Kuo
KHM
,
Layton
DM
,
Lal
A
, et al.
Mitapivat improves markers of erythropoietic activity in long-term study of adults with alpha- or beta-non- transfusion-dependent thalassemia
.
Blood
.
2022
;
140
(
suppl 1
):
2479
2480
.
doi:10.1182/blood-2022-163493
.
20.
Kuo
KHM
,
Layton
D
,
Al-Samkari
H
, et al.
P112: energize and energize-T: two phase 3, randomized, double-blind, placebo-controlled studies of mitapivat in adults with non-transfusion-dependent or transfusion-dependent alpha- or beta-thalassemia
.
Hemasphere
.
2022
Jan
31
;
6(suppl)
:
23
-
24
.
doi:10.1097/01.HS9.0000821540.81071.fa
.
21.
Forsyth
S
,
Schroeder
P
,
Geib
J
, et al.
Safety, pharmacokinetics, and pharmacodynamics of etavopivat (FT-4202), an allosteric activator of pyruvate kinase-R, in healthy adults: a randomized, placebo-controlled, double-blind, first-in-human phase 1 trial
.
Clin Pharm Drug Dev
.
2022
;
11
(
5
):
654
-
665
.
doi:10.1002/cpdd.1058
.
22.
Lal
A
,
Brown
C
,
Coates
T
, et al.
S103: trial in progress: a phase 2, open-label study evaluating the safety and efficacy of the PKR activator etavopivat (FT-4202) in patients with thalassemia or sickle cell disease
.
Hemasphere
.
2022
;
6
(
Suppl
):
2
.
doi:10.1097/01.HS9.0000821380.12178.0d
.
You do not currently have access to this content.