PROOF OF CONCEPT FOR THE ORAL PYRUVATE KINASE ACTIVATOR MITAPIVAT IN ADULTS WITH NON–TRANSFUSION-DEPENDENT THALASSEMIA: INTERIM RESULTS FROM AN ONGOING, PHASE 2, OPEN-LABEL, MULTICENTER STUDY
Author(s): ,
Kevin HM Kuo
Affiliations:
Toronto General Hospital, University Health Network,Toronto,Canada
,
D Mark Layton
Affiliations:
Hammersmith Hospital, Imperial College Healthcare NHS Trust,London,United Kingdom
,
Ashutosh Lal
Affiliations:
UCSF Benioff Children's Hospital Oakland,Oakland,United States
,
Hanny Al-Samkari
Affiliations:
Massachusetts General Hospital, Harvard Medical School,Boston,United States
,
Feng Tai
Affiliations:
Agios Pharmaceuticals, Inc.,Cambridge,United States
,
Megan Lynch
Affiliations:
Agios Pharmaceuticals, Inc.,Cambridge,United States
,
Katrin Uhlig
Affiliations:
Agios Pharmaceuticals, Inc.,Cambridge,United States
Elliot P Vichinsky
Affiliations:
UCSF Benioff Children's Hospital Oakland,Oakland,United States
(Abstract release date: 05/14/20) EHA Library. HM Kuo K. 06/12/20; 295116; S297
Kevin HM Kuo
Kevin HM Kuo
Contributions
Abstract

Abstract: S297

Type: Oral Presentation

Session title: New therapeutic approaches for thalassemia

Background
Thalassemias are characterized by compromised red blood cell (RBC) survival due to mutations in the genes encoding α- and/or β-globins. Imbalanced globin chain production results in excess β- or α-globin precipitation, reduced RBC fitness, and ineffective erythropoiesis and hemolysis. ATP levels are reduced in thalassemic RBCs, despite increased energy demands to support clearance of globin precipitates and maintenance of cell membrane integrity. Mitapivat sulfate (AG-348) is a first-in-class, small-molecule, oral activator of RBC pyruvate kinase (PK-R), a key enzyme regulating ATP production via glycolysis. Glycolysis is the primary means of RBC energy generation. Increasing ATP synthesis via PK-R activation by mitapivat may improve thalassemic RBC fitness and survival, thus ameliorating anemia and other clinical sequelae. In a phase 2 study in patients (pts) with PK deficiency caused by mutations in PK-R, mitapivat increased hemoglobin (Hb) by >1.0 g/dL in 50% of pts (Grace et al. NEJM 2019;381:933). Studies in mouse β-thalassemia models and healthy adults have suggested benefits from activating wild-type PK-R.

Aims
To report interim results from an ongoing study of PK-R activation by mitapivat in adults with non–transfusion-dependent thalassemia (NTDT).

Methods
This open-label, phase 2 study (EudraCT 2018-002217-35/NCT03692052) evaluates the efficacy, safety, pharmacokinetics, and pharmacodynamics of mitapivat in adults with NTDT in a 24-week core treatment period plus optional 2-year extension. Key inclusion criteria: presence of β-thalassemia ± α-globin gene mutations, HbE β-thalassemia, or α-thalassemia (HbH disease); Hb ≤10.0 g/dL; ≤5 RBC units transfused in the preceding 24 weeks and none in the 8 weeks prior to study drug. Pts receive mitapivat 50 mg orally twice daily (BID) for 6 weeks; dosage may increase at week 6 to 100 mg BID, depending on safety. Primary endpoint: proportion of pts who achieve a Hb response (increase of ≥1.0 g/dL from baseline at any time between weeks 4–12, inclusive). Key secondary/exploratory endpoints include sustained or delayed Hb response; markers of hemolysis; hematopoietic activity; iron metabolism and overload; safety and pharmacokinetics.

Results
Nine pts (5 female), all with β-thalassemia, had received mitapivat as of 14Nov2019 (data cut). Mean age was 46 years (range 31–57) and mean baseline Hb was 7.54 g/dL (SD 1.35). All pts received 100 mg BID at week 6; at data cut, 8 pts had completed 12 weeks of treatment and were evaluable for the primary endpoint. Seven of these (87.5%, 90% CI 52.9, 99.4) achieved a Hb increase from baseline of ≥1.0 g/dL after a mean of 3.5 weeks (range 1.4–7.1). The mean Hb increase of responders was 1.76 g/dL (range 0.9–3.3) during weeks 4–12. Responders showed directionally favorable changes in markers of erythropoiesis and hemolysis. The safety profile was consistent with previously published mitapivat studies. There were no serious adverse events (AEs), and no pts discontinued owing to AEs. AEs occurring in ≥2 pts were insomnia, diarrhea, dyspepsia, fatigue, dizziness, cough, headache, upper respiratory tract infection, nasal congestion, and back pain. Additional pts have received mitapivat since the data cut, including pts with α-thalassemia; updated results will be presented.

Conclusion
These data establish proof of concept that activation of wild-type PK-R by mitapivat has potential clinical benefit in thalassemia, and support its further investigation as an oral treatment for pts with β- and α-thalassemia. This study is also the first drug trial aimed at treating anemia in α-thalassemia.

Session topic: 27. Thalassemias

Keyword(s): Clinical trial, Hemolytic anemia, Phase II, Thalassemia

Abstract: S297

Type: Oral Presentation

Session title: New therapeutic approaches for thalassemia

Background
Thalassemias are characterized by compromised red blood cell (RBC) survival due to mutations in the genes encoding α- and/or β-globins. Imbalanced globin chain production results in excess β- or α-globin precipitation, reduced RBC fitness, and ineffective erythropoiesis and hemolysis. ATP levels are reduced in thalassemic RBCs, despite increased energy demands to support clearance of globin precipitates and maintenance of cell membrane integrity. Mitapivat sulfate (AG-348) is a first-in-class, small-molecule, oral activator of RBC pyruvate kinase (PK-R), a key enzyme regulating ATP production via glycolysis. Glycolysis is the primary means of RBC energy generation. Increasing ATP synthesis via PK-R activation by mitapivat may improve thalassemic RBC fitness and survival, thus ameliorating anemia and other clinical sequelae. In a phase 2 study in patients (pts) with PK deficiency caused by mutations in PK-R, mitapivat increased hemoglobin (Hb) by >1.0 g/dL in 50% of pts (Grace et al. NEJM 2019;381:933). Studies in mouse β-thalassemia models and healthy adults have suggested benefits from activating wild-type PK-R.

Aims
To report interim results from an ongoing study of PK-R activation by mitapivat in adults with non–transfusion-dependent thalassemia (NTDT).

Methods
This open-label, phase 2 study (EudraCT 2018-002217-35/NCT03692052) evaluates the efficacy, safety, pharmacokinetics, and pharmacodynamics of mitapivat in adults with NTDT in a 24-week core treatment period plus optional 2-year extension. Key inclusion criteria: presence of β-thalassemia ± α-globin gene mutations, HbE β-thalassemia, or α-thalassemia (HbH disease); Hb ≤10.0 g/dL; ≤5 RBC units transfused in the preceding 24 weeks and none in the 8 weeks prior to study drug. Pts receive mitapivat 50 mg orally twice daily (BID) for 6 weeks; dosage may increase at week 6 to 100 mg BID, depending on safety. Primary endpoint: proportion of pts who achieve a Hb response (increase of ≥1.0 g/dL from baseline at any time between weeks 4–12, inclusive). Key secondary/exploratory endpoints include sustained or delayed Hb response; markers of hemolysis; hematopoietic activity; iron metabolism and overload; safety and pharmacokinetics.

Results
Nine pts (5 female), all with β-thalassemia, had received mitapivat as of 14Nov2019 (data cut). Mean age was 46 years (range 31–57) and mean baseline Hb was 7.54 g/dL (SD 1.35). All pts received 100 mg BID at week 6; at data cut, 8 pts had completed 12 weeks of treatment and were evaluable for the primary endpoint. Seven of these (87.5%, 90% CI 52.9, 99.4) achieved a Hb increase from baseline of ≥1.0 g/dL after a mean of 3.5 weeks (range 1.4–7.1). The mean Hb increase of responders was 1.76 g/dL (range 0.9–3.3) during weeks 4–12. Responders showed directionally favorable changes in markers of erythropoiesis and hemolysis. The safety profile was consistent with previously published mitapivat studies. There were no serious adverse events (AEs), and no pts discontinued owing to AEs. AEs occurring in ≥2 pts were insomnia, diarrhea, dyspepsia, fatigue, dizziness, cough, headache, upper respiratory tract infection, nasal congestion, and back pain. Additional pts have received mitapivat since the data cut, including pts with α-thalassemia; updated results will be presented.

Conclusion
These data establish proof of concept that activation of wild-type PK-R by mitapivat has potential clinical benefit in thalassemia, and support its further investigation as an oral treatment for pts with β- and α-thalassemia. This study is also the first drug trial aimed at treating anemia in α-thalassemia.

Session topic: 27. Thalassemias

Keyword(s): Clinical trial, Hemolytic anemia, Phase II, Thalassemia

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