Pyruvate kinase deficiency (PKD) disease correction therapy! EU approves the first oral PK allosteric activator Pyrukynd (mitapivat)!

Nov.
12, 2022 /Biovalley BIOON/ -- Agios Pharmaceuticals has announced that the European Commission (EC) has approved Pyrukynd (mitapivat) for the treatment of adult patients
with pyruvate kinase deficiency (PKD).
In February 2022, Pyrukynd was approved by the US FDA for the treatment of hemolytic anemia
in adult patients with PKD.
In both the United States and the European Union, Pyrukynd has previously been granted orphan drug designation (ODD).

Pyrukynd is a first-in-class oral pyruvate kinase (PK) activator and the first disease-modifying therapy (DMT)
to treat PKD.
Data from the Phase 3 ACTIVATE and ACTIVATE-T studies showed that Pyrukynd treatment significantly improved hemolysis and anemia and reduced transfusion burden
in adult patients with PKD, including those who did not receive regular transfusions and those who received regular transfusions.

PKD is a rare, debilitating, lifelong hemolytic anaemia characterized by serious complications
affecting multiple organs, regardless of the patient's transfusion status.
PKD can cause chronic fatigue, hemolytic crisis, gallstones, splenomegaly, cirrhosis, pulmonary hypertension, and osteoporosis, and the burden of disease affects a patient's ability to manage work and other daily activities, as well as mental health
.

The active pharmaceutical ingredient of Pyrukynd, mitapivat, is a first-in-class, oral, small molecule allosteric activator that works
by allosteric binding PK tetramer and increasing PK activity.
In patients with PKD, mutations in the gene encoding erythrocyte pyruvate kinase (PK-R) result in decreased adenosine triphosphate (ATP), shortened red blood cell lifespan, and chronic hemolysis
.

MITAPIVAT Chemical Structure (Image source: rechemscience.
com)

Pyruvate kinase deficiency (PKD) is a rare genetic disorder manifested by chronic hemolytic anemia, an accelerated destruction
of red blood cells.
Inherited mutations in the PK-R gene result in a lack of cellular energy within erythrocytes, manifested by decreased pyruvate kinase (PK) enzyme activity, decreased adenosine triphosphate (ATP) levels, and accumulation
of upstream metabolites, including 2,3-DPG [2,3-bisphosphoglycerides].

PKD can cause serious complications, including gallstones, pulmonary hypertension, extramedullary haematopoiesis, osteoporosis and iron overload, and their sequelae, which can occur
regardless of the degree of anaemia or transfusion burden.
PKD can also lead to quality of life issues, including challenges
in work and school activities, social life, and emotional health.

Treatment options for PKD are very limited
.
Current strategies for the treatment of PKD, including red blood cell transfusion and splenectomy, are associated with both short- and long-term risks, including iron overload, blood clots, and an increased
risk of infection.
Pyrukynd has been shown to have clinical benefits in patients with PKD, regardless of their transfusion burden
.

Mechanism of action of mitapivat (click on the image for a larger image)

Approval of Pyrukynd by US and European regulatory agencies is based on the results of
2 pivotal Phase 3 clinical studies (ACTIVATE, ACTIVATE-T).
The ACTIVATE study, conducted in adult patients with PKD who did not receive regular blood transfusions, showed that the primary endpoint was met: 40% of patients in the Pyrukynd-treated group achieved hemoglobin remission (defined as a sustained increase in hemoglobin from baseline ≥ 1.
5 g/dL) compared to 0 (bilateral p<0.
0001)<b11> in the placebo group.

The ACTIVATE-T study was conducted in adult patients with PKD who received regular blood transfusions, and the results showed that during the 24-week fixed dose period, 37% (n=10) of patients achieved a reduction in transfusion burden of ≥33% compared with the individual's historical transfusion burden (unilateral p=0.
0002), and 22% (n=6) of patients did not have blood
transfusion.
In two studies, the safety profile of Pyrukynd was consistent
with previously reported data.

Based on the results of the ACTIVATE and ACTIVATE-T Phase 3 trials, Pyrukynd can have a meaningful impact
on PKD patients.
Currently, treatment options for PKD are very limited, and Pyrukynd has demonstrated potential clinical benefit for patients with PKD, regardless of their transfusion burden
.

A comprehensive analysis of data from two studies, including patient-reported outcomes [PRO], was presented
at the 2021 European Association of Haematology (EHA) online meeting.

Agios is currently conducting an extended study in adult patients with PKD who previously participated in the ACTIVATE study or the ACTIVATE-T study to evaluate the long-term safety, tolerability and efficacy
of Pyrukynd treatment.
Meanwhile, Agios is recruiting pediatric PKD patients to participate in two pivotal studies, ACTIVATE-kids (patients with irregular blood transfusions) and ACTIVATE-kidsT (patients with regular blood transfusions).

(Biovalley Bioon.
com)

PYRUKYND (mitapivat) Approved in the EU for the Treatment of Pyruvate Kinase (PK) Deficiency in Adult Patients