Summary
Non‐transfusion‐dependent thalassaemia (NTDT) can result in serious complications and comorbidities that can impact patients' quality of life. Mitapivat, a first‐in‐class, oral, small‐molecule allosteric activator of red blood cell pyruvate kinase, is under investigation in adults with thalassaemia. Through its mechanism of action, mitapivat increases adenosine triphosphate, leading to improvements in red blood cell health, ineffective erythropoiesis and haemolysis. An open‐label, multicentre, phase 2 study (NCT03692052) is evaluating mitapivat 100 mg twice daily in adults with NTDT. We previously reported a statistically significant haemoglobin response (a ≥1.0 g/dL increase in haemoglobin concentration from baseline at ≥1 assessments between Weeks 4 and 12 [inclusive]) during the 24‐week core period. Here, we report efficacy and safety results up to Week 156 and to data cut‐off date respectively. Of 20 patients enrolled, 17 continued in the extension period. Median change from baseline in haemoglobin concentration at Week 156 was 1.2 g/dL. Patients receiving mitapivat demonstrated sustained improvements in haemoglobin concentrations and markers of erythropoietic activity, haemolysis and iron homeostasis. Five patients (29%) had a grade ≥3 treatment‐emergent adverse event; none were considered treatment related. Treatment with mitapivat was well tolerated, with a safety profile consistent with previous studies of mitapivat in pyruvate kinase deficiency.
Keywords: efficacy, mitapivat, non‐transfusion‐dependent thalassaemia, pyruvate kinase, safety
Mitapivat is an oral activator of pyruvate kinase (PK), the enzyme responsible for the final step in glycolysis, and increases production of adenosine triphosphate (ATP), which may lead to improvements in red blood cell health, ineffective erythropoiesis and haemolysis. Topline data from the phase 2 study (NCT03692052) established proof of concept for PK activation as a therapeutic approach to improve anaemia in patients with α‐ or β‐thalassaemia. In the study's extension period, patients receiving mitapivat demonstrated sustained improvements in haemoglobin (Hb) concentrations (durable in the extension period through Week 156) and markers of erythropoietic activity, haemolysis and iron homeostasis (generally improved or stable through Week 120). The long‐term data provide additional support for mitapivat as a potential therapeutic approach in patients with α‐ or β‐thalassaemia, addressing an important unmet need. ADP, adenosine diphosphate; DPG, diphosphoglycerate; FBP, fructose bisphosphate; PEP, phosphoenolpyruvate; PG, phosphoglycerate.
INTRODUCTION
Thalassaemia is an inherited red blood cell disorder caused by mutations in the α‐ and/or β‐globin genes that lead to deficiencies in globin production, creating an imbalance of α‐ and β‐globin chains. 1 Estimates for global prevalence of clinically significant forms of thalassaemia are limited and vary geographically. 2 , 3 However, while thalassaemia has historically been more prevalent in Mediterranean countries, the Middle East and Southeast Asia, recent migration patterns from these regions to the United States and Northern Europe have started to shift the global prevalence pattern, with a major increase in non‐transfusion‐dependent thalassaemia (NTDT) in several regions. 4 , 5 , 6 , 7
The catalytic activity of the PK isozyme expressed in red blood cells (PKR) is essential for their health because mature red blood cells lack mitochondria and are therefore primarily dependent on glycolysis for the production of ATP. 8 , 9 , 10 , 11 In thalassaemia, the imbalance between α‐ and β‐globin leads to excess unpaired globin chains, which aggregate and precipitate, causing the formation of reactive oxygen species. 12 , 13 , 14 Generation of adenosine triphosphate (ATP) by glycolysis is essential for maintaining red blood cell health; however, ATP levels in thalassaemic red blood cells are insufficient to meet the increased energy demands associated with protein degradation and cellular oxidative stress responses. 8 , 9 , 10 The ensuing increase in metabolic stress leads to disruption of the red blood cell membrane and shortened cell survival, resulting in ineffective erythropoiesis, chronic haemolytic anaemia and dysregulated iron homeostasis. 1 , 11 , 15
Although patients with NTDT do not require routine blood transfusions for survival, they can still experience increased morbidity, premature mortality and a diminished quality of life due to the considerable burden of disease‐related complications and comorbidities that correlate with lower haemoglobin concentrations. 16 , 17 , 18 , 19 , 20 Current options to manage complications of NTDT are occasional—or even frequent—transfusions and iron chelation therapy. 21 Though not an approved treatment for NTDT, hydroxyurea is an oral therapy that is widely used and beneficial in some patients. 21 Approved therapies for the treatment of the ineffective erythropoiesis and haemolytic anaemia associated with NTDT are limited to patients with β‐thalassaemia, with no oral options; no disease‐modifying agents are currently available for patients with α‐thalassaemia. 22 , 23
Mitapivat is a first‐in‐class, oral, small‐molecule allosteric activator of pyruvate kinase (PK), an enzyme that regulates the glycolytic pathway, and increases ATP generation. This therapy is approved in the United States by the US Food and Drug Administration for the treatment of haemolytic anaemia in adults with PK deficiency 4 and in the European Union by the European Medicines Agency and in Great Britain by the Medicines and Healthcare Products Regulatory Agency for the treatment of PK deficiency in adults. 24 It is under clinical investigation in α‐ and β‐thalassaemia. An open‐label, multicentre, phase 2 study that includes a 24‐week core period (completed) 25 followed by an extension period (up to 10 years; ongoing) is evaluating the efficacy and safety of mitapivat in adult patients with NTDT (NCT03692052). We previously reported that during the core 24‐week period, the primary end‐point—haemoglobin response (a ≥1.0 g/dL increase in haemoglobin concentration from baseline at ≥1 assessments between Week 4 and Week 12, inclusive)—was met in 80% of patients. 25 Here, we present the long‐term efficacy and safety results of the extension period up to Week 156 and through the data cut‐off respectively.
METHODS
Study design and population
The study design and patient inclusion/exclusion criteria of this phase 2, open‐label multicentre trial have been previously reported. 25 Patients who completed the 24‐week core period and achieved a haemoglobin response or a delayed haemoglobin response (a ≥1.0 g/dL increase in haemoglobin concentration from baseline at ≥1 assessments after Week 12) with no ongoing grade ≥ 3 treatment‐emergent adverse event (TEAE) related to study drug had the option to continue treatment with mitapivat 100 mg twice daily in the 10‐year extension period. Scheduled assessments include haemoglobin concentration every 12 weeks from Week 24 to Week 132 and every 24 weeks thereafter; levels of markers of erythropoietic activity, haemolysis and iron homeostasis and clinical laboratory and safety assessments every 24 weeks from Week 24 to Week 120, at Week 132 and every 24 weeks thereafter; and dual‐energy X‐ray absorptiometry scans for measuring bone mineral density at the lumbar spine and proximal femur at Week 24, Week 72, Week 120, Week 180 and every 48 weeks thereafter. Information regarding AEs and other safety assessments was also continuously collected. The data cut‐off date for this analysis was 16 February 2023. Haemoglobin concentration is analysed and reported through Week 156. Due to COVID‐19‐related factors and differences in scheduled assessment time points, markers of erythropoietic activity, haemolysis and iron homeostasis are reported through Week 120. Safety data, including bone mineral density data, are reported up to the data cut‐off date (16 February 2023).
Outcomes
Outcomes analysed during the extension period include median change from baseline in haemoglobin concentration and in markers of erythropoietic activity, haemolysis and iron homeostasis (erythropoietin, erythroferrone, lactate dehydrogenase, indirect bilirubin, reticulocyte count, soluble transferrin receptor, hepcidin and liver iron) over the duration of the extension period. Safety outcomes in the extension period include type, incidence and severity of adverse events (AEs) and TEAEs; TEAEs leading to study drug dose reduction, interruption or discontinuation; and changes in clinical laboratory tests, physical examination and 12‐lead electrocardiogram findings, bone mineral density of the lumbar spine and proximal femur and vital signs.
Statistical analysis
Efficacy and safety outcomes were evaluated in the analysis set that includes all patients who received at least one dose of the study drug during the extension period. Continuous variables are summarized using descriptive statistics (i.e. number of non‐missing values, mean [standard deviation], median [quartiles] and minimum, maximum). Categorical variables are summarized by frequency distributions (number and percentage of patients within a given category in the analysis dataset). Descriptive analyses of safety are reported. For bone mineral density, the worst T‐score (number of standard deviations away from the mean for a healthy person of the same sex) 26 or the worst Z‐score (number of standard deviations away from the mean of a young person of the same age and sex) 26 of the measurements at the lumbar spine and proximal femur and their changes from baseline values are summarized for each individual patient and at each scheduled time point.
RESULTS
Disposition and demographics
Seventeen of the 20 patients from the core period (α‐thalassaemia [n = 4]; β‐thalassaemia [n = 13]) continued into the extension period and received at least one dose of study drug during the extension period (Figure 1). Demographics and baseline characteristics are shown in Table 1. At data cut‐off, the median (range) duration of treatment was 142.9 (40.0, 179.9) weeks. The median (range) age of patients was 44 (29, 67) years; 12 (71%) patients were female and 8 (47%) identified as Asian. Median (range) baseline haemoglobin concentration was 8.5 (5.6, 9.8) g/dL. As has been previously reported, a wide range of genotypes was observed, including β‐thalassaemia intermedia, HbE/β‐thalassaemia, and deletional and non‐deletional haemoglobin H (HbH) disease. 25
FIGURE 1.
Study disposition. The efficacy and safety analysis sets include all patients who received ≥1 dose of mitapivat. *Data cut‐off, 16 February 2023. †2 patients withdrew consent, and one patient discontinued due to investigator decision. AE, adverse event.
TABLE 1.
Demographics and baseline characteristics of patients who entered the extension period. a
| Patient demographics and baseline b characteristics | All patients (N = 17) |
|---|---|
| Duration of treatment, weeks | 142.9 (40.0, 179.9) |
| Sex, n (%) | |
| Male | 5 (29) |
| Female | 12 (71) |
| Age, years | 44 (29, 67) |
| Race, n (%) | |
| Asian | 8 (47) |
| White | 4 (24) |
| Native Hawaiian or other Pacific Islander | 1 (6) |
| Other | 3 (18) |
| Not reported | 1 (6) |
| Thalassaemia type, n (%) | |
| α‐thalassaemia | 4 (24) |
| β‐thalassaemia | 13 (77) |
| Haemoglobin, g/dL | 8.5 (5.6, 9.8) |
| <8.5 g/dL, n (%) | 8 (47) |
| ≥8.5 g/dL, n (%) | 9 (53) |
| Total bilirubin, mg/dL | 1.9 (0.5, 5.3) |
| Indirect bilirubin, mg/dL | 1.2 (0.26, 5.52) |
| Previous splenectomy, n (%) | |
| Yes | 2 (12) |
| No | 15 (88) |
| Previous chelation status, n (%) | |
| Yes | 3 (18) |
| No | 14 (82) |
| Lactate dehydrogenase, U/L | 245.0 (126.0, 513.0) |
| Erythropoietin, IU/L | 70.5 (15.0, 11 191.0) |
| Reticulocyte count, ×109/L | 157.5 (48.9, 400.0) |
| Soluble transferrin receptor, mg/dL | 1.4 (0.5, 2.7) |
| Hepcidin, ng/L | 41 300 (18 950, 100 300) |
Note: Continuous variables are listed as median (range), unless otherwise specified.
Abbreviations: IU, international units; U, units.
Patients who completed the 24‐week core period and achieved a haemoglobin response or a delayed haemoglobin response (a ≥1.0 g/dL increase in haemoglobin concentration from baseline at ≥1 assessments after Week 12) with no ongoing grade ≥3 treatment‐emergent adverse event related to study drug had the option to continue treatment with mitapivat 100 mg twice daily in the 10‐year extension period.
Baseline parameter concentration is defined as the average of all available concentrations during the screening period and up to the first dose of the study drug.
Efficacy
For the 17 patients who continued in the extension period, the median increase in haemoglobin concentration from baseline to Week 24 (end of the core period) was 1.2 g/dL. Increases in haemoglobin concentration ≥1.0 g/dL observed at Week 24 were durable in the extension period at Weeks 48, 72, 84, 96, 108, 120, 132 and 156 (Figure 2). Improvements in markers of erythropoietic activity and haemolysis were indicated by a decrease from baseline and were observed by Week 24 (Figure 3A–E). These improvements were durable for several markers and decreased even further for some during the extension period (from Weeks 24 to 120). At Week 120, the markers with sustained improvement (median [Q1, Q3]) were erythropoietin (IU/L), −15.00 (−63.00, 5.00); lactate dehydrogenase (U/L), −14.50 (−107.00, 17.50); and reticulocytes (%), −1.03 (−1.55, −0.68). Further decreases were noted for erythroferrone and indirect bilirubin during the extension period, −5015.0 ng/L (−17 630.0, −2385.0) and − 0.93 mg/dL (−1.48, −0.53) respectively. During the extension period, the levels of markers of iron homeostasis remained stable or improved (Figure 3F–H). A decrease in the change from baseline (median [Q1, Q3]) in soluble transferrin receptor (mg/dL) was observed at Week 24 with the improvement sustained until Week 120 (−0.15 [−0.39, 0]), while hepcidin (ng/L) and liver iron concentration (mg/g dry weight) remained stable throughout both the duration of treatment (2750.0 [−11 200.0, 43 550.0] and −0.55 [−2.40, 0.00] respectively).
FIGURE 2.
Change from baseline in haemoglobin concentration through the extension period. Shaded area = extension period; 
= 1.0 g/dL increase in haemoglobin concentration from baseline value.
FIGURE 3.
Erythropoietic activity, haemolysis and iron homeostasis through the extension period. Data shown are change from baseline in markers of erythropoietic activity, haemolysis, through the extension period. (A) Erythropoietin; (B) erythroferrone; (C) lactate dehydrogenase; (D) indirect bilirubin; (E) percent reticulocytes; (F) soluble transferrin receptor; (G) hepcidin; (H) liver iron. Note that due to COVID‐19‐related factors and differences in scheduled assessment time points, markers of erythropoietic activity, haemolysis and iron homeostasis were analysed through Week 120. Shaded area = extension period. dw, dry weight.
Safety
During the extension period (to data cut‐off date), mitapivat was generally well tolerated, and no new safety signals were identified (Table 2). Five (29%) patients had a TEAE that was grade 3 or higher; none were considered to be treatment‐related. The most frequent TEAEs (occurring in ≥15% of patients; n [%]) reported during the extension period included headache (8 [47%]), arthralgia (8 [47%]) and fatigue (7 [41%]); (Table 3). The most commonly reported TEAE in the core period (and the only grade 3 or worse TEAE to be considered treatment related) was initial insomnia (difficulty falling asleep, as opposed to staying asleep or waking up early), 27 with a median duration of 34.0 days. 25 During the extension period, initial insomnia was not reported by any patient. No trends for decreases in bone mineral density (BMD) were observed (Figure 4). No deaths were observed.
TABLE 2.
Overview of treatment‐emergent adverse events (TEAEs).
| Category | Patients with event in core period, n (%) (N = 20) weeks 0–24 | Patients with event in extension period, n (%) (N = 17) weeks ≥25 a |
|---|---|---|
| Treatment‐related TEAEs | 13 (65) | 4 (24) |
| Grade ≥ 3 TEAEs | 5 (25) | 5 (29) b |
| Grade ≥ 3 treatment‐related TEAEs | 1 (5) | 0 |
| Serious TEAEs | 1 (5) | 2 (12) |
| Serious treatment‐related TEAEs | 0 | 0 |
| TEAEs leading to study drug | ||
| Dose reduction | 3 (15) | 2 (12) |
| Interruption | 1 (5) | 0 |
| Discontinuation | 1 (5) | 0 |
Data cut‐off: 16 February 2023; median (range) duration of treatment 142.9 (40.0, 179.9) weeks.
All grade ≥ 3 TEAEs in the extension period were considered unrelated to the study drug. This includes one patient with an ongoing TEAE of haemolysis (patient had undergone cardiac surgery prior to the event). Other grade ≥ 3 TEAEs include one patient with arthralgia, one patient with depression and suicidal ideation, one patient with aortic valve, mitral valve and tricuspid valve diseases and one patient with hyperuricaemia.
TABLE 3.
Most common (any grade in ≥15% of patients in either period) treatment‐emergent adverse events.
| n (%) | Core period (N = 20)weeks 0–24 | Extension period (N = 17) weeks ≥25 a |
|---|---|---|
| Patients with any event | 18 (90) | 17 (100) |
| Dizziness | 6 (30) | 2 (12) |
| Headache | 5 (25) | 8 (47) |
| Fatigue | 4 (20) | 7 (41) |
| Cough | 4 (20) | 5 (29) |
| Pain in extremity | 4 (20) | 5 (29) |
| Dyspepsia | 4 (20) | 3 (18) |
| Diarrhoea | 4 (20) | 2 (12) |
| Nasal congestion | 4 (20) | 0 |
| Upper respiratory tract infection | 4 (20) | 0 |
| Nausea | 3 (15) | 4 (24) |
| Abdominal pain | 3 (15) | 1 (6) |
| Pain | 3 (15) | 1 (6) |
| Oropharyngeal pain | 3 (15) | 1 (6) |
| Ocular icterus | 3 (15) | 0 |
| Abdominal distension | 3 (15) | 1 (6) |
| Back pain | 2 (10) | 5 (29) |
| Vomiting | 2 (10) | 3 (18) |
| Initial insomnia | 10 (50) | 0 |
| Arthralgia | 1 (5) | 8 (47) |
| Pruritus | 1 (5) | 3 (18) |
| COVID‐19 | 0 | 4 (24) |
| Urinary tract infection | 0 | 4 (24) |
| Alanine aminotransferase increased | 0 | 3 (18) |
| Influenza‐like illness | 0 | 3 (18) |
| Migraine | 0 | 3 (18) |
Data cut‐off, 16 February 2023; median (range) duration of treatment, 142.9 (40.0, 179.9) weeks.
FIGURE 4.
Bone mineral density through the extension period. Individual longitudinal plots of (A) worst T‐score (lumbar spine and proximal femur) in men aged ≥50 years and women of non‐childbearing potential (FSH >35 mIU/mL, hysterectomy and/or confirmed menopausal; n = 5); normal BMD>−1, osteopenia −1 to −2.5, osteoporosis >−2.5 and (B) worst Z‐score (lumbar spine and proximal femur) in men aged <50 years and women of childbearing potential (FSH ≤35 mIU/mL and no history of hysterectomy or menopause; n = 12); normal BMD > −2, low BMD < −2. BMD, bone mineral density; FSH, follicle‐stimulating hormone.
DISCUSSION
In preclinical studies, mitapivat increased ATP; reduced 2,3‐diphosphoglycerate; improved markers of ineffective erythropoiesis, haemolysis and iron homeostasis; and improved anaemia. 28 , 29 , 30 In this phase 2, open‐label, extension study of patients with thalassaemia receiving mitapivat 100 mg twice daily, durable improvements in haemoglobin concentration were observed through Week 156.
In a retrospective study of 63 patients with non‐transfusion‐dependent (NTD) β‐thalassaemia, the mean haemoglobin level was significantly lower in patients with a morbidity compared to those without a morbidity (morbidities included extramedullary haematopoietic pseudotumours, pulmonary hypertension, venous thromboembolism, heart failure, leg ulcers, abnormal liver function, diabetes mellitus, hypothyroidism, hypogonadism and osteoporosis). 16 There was a significant negative correlation between haemoglobin level and the number of morbidities, and a significant and strong correlation between each 1 g/dL change in haemoglobin level and the odds of morbidity development (odds ratio [95% confidence interval] with each 1 g/dL increase = 0.31 [0.17 to 0.56]). 16 In a retrospective analysis of approximately 2000 patients with NTDT, survival was shown to be significantly worse in patients who remained non‐regularly transfused compared to patients who later converted to regular transfusions (p < 0.001). 22 Furthermore, a recent 10‐year retrospective cohort study of 53 patients with NTD β‐thalassaemia showed a significantly higher 10‐year cumulative morbidity‐free survival rate of 78.6% for patients with haemoglobin level ≥ 10 g/dL, compared with 13.2% for those with haemoglobin level < 10 g/dL. 20 Each 1 g/dL increase in baseline haemoglobin level was associated with a 28% reduction in morbidity risk. 20 Therefore, these previous studies suggest that mitapivat may provide clinical benefit by improving anaemia, reducing the risk for developing comorbidities and potentially preventing the need for chronic transfusions (to manage worsening anaemia) in many patients with NTDT. 31
In this study, increases in haemoglobin concentration were observed together with improvements in markers of erythropoietic activity, haemolysis and iron homeostasis. In thalassaemia, erythropoietin levels are increased due to anaemia and hypoxia. 15 , 32 , 33 Circulating erythropoietin binds to the erythropoietin receptor on erythroid progenitor cells, leading to the stimulation of Janus kinase 2, 33 which in turn drives pathological extramedullary erythropoiesis. 15 , 33 , 34 With expanded erythropoiesis, the concentration of soluble transferrin receptors is increased. 35 The overall results indicate that the rise in haemoglobin is not caused by increased marrow activity, but decreased ineffective erythropoiesis and improved red cell survival. Our observed durable reductions in concentrations of erythropoietin and soluble transferrin receptor may indicate a trend towards the normalization of erythropoietic activity and improved red blood cell quality. 36
In thalassaemia, increased levels of bilirubin may result from ineffective erythropoiesis in the bone marrow, increased haemoglobin catabolism, decreased hepatic clearance and extravascular haemolysis. 37 Elevated levels of lactate dehydrogenase result from increased intravascular haemolysis. 38 The number of reticulocytes in the bloodstream increases due to an increased release of immature reticulocytes from the bone marrow in response to elevated erythropoietic stimulation. 39 Decreases in these markers of haemolysis were observed through Week 120. During the increased erythropoietic activity observed in thalassaemia, increased erythroferrone suppresses hepcidin production, thereby mediating iron overload. 40 We observed decreased levels of erythroferrone that were durable through Week 120. Overall, hepcidin levels generally remained stable.
Mitapivat was generally well tolerated during the extension period, and there were no new safety signals. From baseline to Week 180, there were only minor changes in T‐scores and Z‐scores, indicating no decreases in BMD that required clinical management. Initial insomnia was reported by 10 (50%) patients during the core treatment period and by no patients during the extension period. However, the absence of a placebo group in this study precludes a full understanding of the association of insomnia with mitapivat in the context of thalassaemia.
The increase in ATP induced by mitapivat may reduce oxidative stress, improve both red blood cell fitness and survival, improve erythropoietic activity and reduce haemolysis, thereby potentially addressing the root pathophysiology of thalassaemia. Limitations of this study include the single‐arm, open‐label trial design without a control group, and the small population size, which restricts the assumptions that can be surmised. Changes in markers of erythropoietic activity, haemolysis and iron homeostasis were continuous variables that were summarized using descriptive statistics only. The small number of transfusions at baseline and throughout the study period precludes interpretation of the effect of mitapivat on transfusion requirement. This study took place during the COVID‐19 pandemic, and missing data make it difficult to interpret the visual trends observed over time in changes from baseline in markers of erythropoietic activity, haemolysis and iron homeostasis. At data cut‐off, BMD data were only available for six patients through Week 180. Safety analysis was limited to a comparison between the core period (24 weeks) and the extension period (Weeks 25–156), resulting in uneven comparison periods.
CONCLUSIONS
Patients with NTDT are at risk for under‐recognized disease burden and comorbidities. Mitapivat, through its hypothesized mechanism of action, may improve red blood cell health, as well as ineffective erythropoiesis, haemolysis and iron homeostasis. Despite the heterogeneity of the patients' α‐ or β‐globin genotype, improvements in haemoglobin concentrations observed during the core period were durable throughout the extension period through Week 156. Markers of erythropoietic activity, haemolysis and iron homeostasis were also generally improved or stable through Week 120. No new safety signals were identified in the extension period. These results support continued evaluation of mitapivat in patients with NTDT. Two ongoing phase 3, double‐blind, randomized, placebo‐controlled, multicentre trials are evaluating the efficacy and safety of mitapivat in patients with transfusion‐dependent α‐ or β‐thalassaemia (ENERGIZE‐T; NCT04770779) and in patients with NTD α‐ or β‐thalassaemia (ENERGIZE; NCT04770753).
AUTHOR CONTRIBUTIONS
All authors approved the manuscript for submission. KHMK, DML, AL, HA‐S and EPV: Study conceptualization and design, data acquisition and interpretation and manuscript reviewing and editing. JLD, JHE, KSG, GMP and SS: Data interpretation and manuscript reviewing and editing.
FUNDING INFORMATION
This study was funded by Agios Pharmaceuticals.
CONFLICT OF INTEREST STATEMENT
KHMK: Agios, Alexion, Apellis, bluebird bio, Celgene, Pfizer, Novartis—consultancy; Alexion, Novartis—honoraria; Bioverativ—membership on an entity's Board of Directors or advisory committees; Pfizer—research funding. DML: Agios, MINA Therapeutics, Pfizer—membership on an entity's Board of Directors or advisory committees. AL: bluebird bio, Celgene, Insight Magnetics, La Jolla Pharmaceutical Company, Novartis, Protagonist Therapeutics, Terumo Corporations—research funding; Agios, Chiesi USA—consultancy; Celgene, Protagonist Therapeutics—membership on an entity's Board of Directors or advisory committees. HA‐S: Agios, argenx, Sobi, Novartis, Pharmacosmos, Moderna, Forma—consultancy; Agios, Amgen, Sobi, Vaderis, Novartis—research funding. JLD, SS, GMP, KSG, and JHE: employees and shareholders of Agios Pharmaceuticals. EPV: Agios, bluebird bio, Global Blood Therapeutics, Novartis, Pfizer—consultancy and research funding.
ETHICS STATEMENT
The study was conducted in accordance with the ethical principles outlined in the Declaration of Helsinki. The protocol and informed consent forms were reviewed and approved by each study site's institutional review board or institutional ethics committee before the start of the study.
PATIENT CONSENT STATEMENT
All study participants provided written informed consent for participation, including before screening procedures.
CLINICAL TRIAL REGISTRATION (INCLUDING TRIAL NUMBER)
A Phase 2, open‐label, multicentre study to determine the efficacy, safety, pharmacokinetics, and pharmacodynamics of AG‐348 in adult subjects with non‐transfusion‐dependent thalassaemia (ClinicalTrials.gov identifier: NCT03692052).
Supporting information
Table S1.
ACKNOWLEDGEMENTS
We thank the patients, their families and all investigators involved in this study. Medical editorial support, including figure preparation, formatting, proofreading and submission, was provided by Matt Brown, PhD, and Linda M Ritter, PhD (Symbiotix, New York City, NY) and Samantha Forster (Obsidian Healthcare Group, London, UK); supported by Agios Pharmaceuticals.
Kuo KHM, Layton DM, Lal A, Vichinsky EP, Dahlin JL, Shen S, et al. Long‐term efficacy and safety of mitapivat in non‐transfusion‐dependent α‐ or β‐thalassaemia: An open‐label phase 2 study. Br J Haematol. 2025;206(6):1764–1773. 10.1111/bjh.20058
DATA AVAILABILITY STATEMENT
Qualified researchers may request access to related clinical study documents. Please send your data sharing requests to datasharing@agios.com. The following considerations will be taken into account as part of the review: ability for external researchers to re‐identify trial participants, such as small rare disease trials or single‐centre trials; language used in data and requested documents (e.g. English or other); informed consent language with respect to allowance for data sharing; plan to re‐evaluate safety or efficacy data summarized in the approved product labelling; and potential conflict of interest or competitive risk.
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Associated Data
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Supplementary Materials
Table S1.
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