Agios’s PKR Activator, Mitapivat’s strategy for Sickle Cell Disease (SCD)

Agio Pharmaceutical received the Fast Track designation from the USFDA and an orphan drug designation to its first class mitapivat pyruvate kinase-R (PKR) activator from both the USFDA and EMA.

Mitapivat (AG348) Mechanism of Action

Mitapivat (AG348) is a first-class small molecule, and oral allosteric activator of wild-type and a variety of mutated pyruvate kinase-R (PKR) enzymes that has given promising signals to reduce 2,3-diphosphoglycerate (2, 3 -DPG) and increase adenosine triphosphate (ATP) and further leading to the reduction of the polymerization of hemoglobin (Hb) S and the sickle cell of red blood cells.

PKR Activation in Pyruvate Kinase Deficiency, Thalassemia and Sickle Cell Disease

Agios Strategy for Mitapivat (AG348)

Agios JP Morgan Conference, 2020

Mitapivat (AG348) results in Phase I

Technically the Agios is pursuing a simpler approach with the oral small molecule mitapavant and reported results from EHA has suggested that the five of the eight evaluable sickle cell subjects administered up to 50 mg twice a day achieved an increase in hemoglobin of at least 1 g / dl. The trial aims to enroll 25 subjects, dosing up to 100 mg, according to a modified protocol.

Nine patients were enrolled in ongoing Phase I, of which eight completed all expected dose levels except one patient which discontinued it in the first week. Clinical data results showed that seven of the eight (88%) patients who completed all expected dose levels of mitapivat had an increase in Hb, while five of the eight patients (63%) who achieved an increase in hemoglobin of ≥ 1.0 g / dL from baseline (range 1.0-2.7 g / dL). However, mitapivat treatment has been associated with a reduction in hemolytic markers such as bilirubin, lactic acid dehydrogenase and reticulocytes. And as expected, mitapivat showed a decrease in 2,3-DPG and increases in ATP levels were observed, consistent with the proposed mechanism of action and comparable to those observed in healthy voluntary studies with mitapivat.

Along with this, the evaluation of sickle cell curves (t50) and oxygen dissociation curves (p50) was consistent with decreases in sickle cell polymerization and HbS, further supporting the proposed mechanism of action.

The company’s clinical results were supported by pharmacodynamic and biomarker data for mitapivat’s proposed mechanism of action and with two ongoing global, pivotal trials in adults with PK deficiency that are fully enrolled named ACTIVATE and ACTIVATE-T. Agios Pharmaceuticals is focusing on advancing mitapivat to pivotal development, with the goal of initiating a pivotal study by next year.

Clinical Trials of Agios’s Mitapivat therapy

Study Aim	Drug	Indications	NCT Number
Efficacy, Safety, Pharmacokinetics, and Pharmacodynamics of AG-348 in Adult Participants with Non-transfusion-dependent Thalassemia	AG-348	Thalassemia	NCT03692052
Efficacy and Safety of AG-348 in Regularly Transfused Adult Participants With Pyruvate Kinase Deficiency (PKD)	AG-348	Pyruvate Kinase Deficiency|Anemia, Hemolytic	NCT03559699
Safety, Tolerability, Pharmacokinetics, and Pharmacodynamics of Escalating Multiple Oral Doses of AG-348 in Subjects With Stable Sickle Cell Disease	AG-348	Sickle Cell Disease	NCT04000165
Efficacy and Safety of AG-348 in Not Regularly Transfused Adult Participants With Pyruvate Kinase Deficiency (PKD)	AG-348	Pyruvate Kinase Deficiency|Anemia, Hemolytic	NCT03548220
AG-348 in Adult Participants With Pyruvate Kinase (PK) Deficiency	AG-348	Pyruvate Kinase Deficiency	NCT02476916
Extension Study of AG-348 in Adult Participants with Pyruvate Kinase Deficiency Previously Enrolled in AG-348-006 or AG348-C-007	AG-348	Pyruvate Kinase Deficiency	NCT03853798
Pyruvate Kinase Deficiency Global Longitudinal Registry		Pyruvate Kinase Deficiency	NCT03481738

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