Agio Pharmaceutical received an orphan drug designation to (PKR) activator from both the USFDA and EMA.

New York, U.S, 2020-Jul-17 — /EPR Network/ — Agios Pharmaceuticals, shared the proof of clinical concept that has been established based on preliminary analysis in the phase 1 study of mitapivat (AG-348) in patients with sickle cell anemia. 

We, Mellalta Meets would like to touch some key points on clinical findings. 

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. 

FAQs 

How is Agios’s Mitapivat therapy approach for SCD different from other therapies? 

Mitapivat (AG348) is different from other therapies as it works by increasing the activity of PKR and the production of ATP, to avoid red blood cells sickling in SCD by preventing the buildup of 2,3-DPG and maintaining membrane integrity. 

Mitapivat results in Sickle cell Disease? 

Early results from preclinical studies and early clinical studies of mitapivat have shown dose-dependent changes in glycolysis in red blood cells and showed a decrease in 2,3-DPG and increases in ATP levels. These changes were consistent with mitapivat’s mechanism of action and supported his study as a potential treatment for SCD 

What was the reason behind discontinuation of the SCD trial by one patient? 

To date, the ongoing Phase 1 study has enrolled nine patients. Eight patients completed all expected dose levels and one patient discontinued within the first week due to a pre-existing condition and was subsequently lost to follow-up. 

 

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https://mellalta.com/agioss-pkr-activator-mitapivats-strategy-for-sickle-cell-disease-scd/