Effective Date

Date of Origin 

07-01-2024            

Pyrukynd®

(mitapivat)

Tablet

Treatment of hemolytic anemia in adults with pyruvate kinase (PK) deficiency

1

Pyruvate kinase deficiency

Pyruvate kinase deficiency (PKD) is the most common enzyme-related glycolytic defect that results in red cell hemolysis. PKD is characterized by clinical heterogeneity. Heterogeneity results in a variable degree of hemolysis, causing irreversible cellular disruption. Invariably, PKD results in hereditary non-spherocytic anemia. Manifestations occur from the neonatal period through adult life.(2) 

Red blood cell (RBC) metabolism hinges on glycolysis. Pyruvate kinase (PK) enzyme is key to this process. PK converts phosphoenolpyruvate to pyruvate. This step yields 50% of RBC ATP. PK modulates NADH production for methemoglobin reduction. These metabolites enable RBCs to function effectively. In PKD, cellular energy efficiency and longevity decrease. Young RBCs are most affected in PKD. PK expression is controlled by the Pyruvate Kinase L/R (PKLR) gene and follows an autosomal recessive inheritance pattern.(2) 

Cellular integrity of RBCs is maintained by membrane-bound ATPases that exchange sodium for potassium. The sodium and potassium exchange maintains transcellular electrochemical neutrality, cellular fluid balance, and deformability. The absence of the PK enzyme results in a decrease in RBC ATP production, which results in RBC deformability. Intracellular potassium and water loss also occur and results in RBC damage. PKD manifests with enzyme levels of less than 25%. Splenic and hepatic capillaries trap defective RBCs. Extravascular hemolysis occurs, causing hepatosplenomegaly. Intravascular hemolysis may also occur, causing hemoglobinuria. Anemia underlies the progressive fatigue in PKD. Increased 2,3-diphosphoglycerate (2.3-DPG) causes oxygen unloading in tissues. This shifts the oxygen dissociation curve rightward. Elevated 2,3-DPG helps compensate for anemia.(2) 

Testing for PK deficiency can be done by measuring PK activity in RBCs (biochemical testing) and/or by identifying a pathogenic PKLR gene mutation (genetic testing). The most direct evidence of functional PK deficiency is by biochemical testing, unless the patient has had a recent transfusion since the transfused RBCs will have normal activity and can make the patient’s results appear normal. The diagnosis of PKD is confirmed in a patient with hemolytic anemia (or compensated hemolysis) who has laboratory evidence of reduced RBC PK enzymatic activity and/or genetic evidence or pathogenic PKLR mutations.(3) The differential diagnoses of PKD include ruling out other causes of hemolytic anemia, e.g., antibody or immune hemolysis, or enzyme deficiencies.(2) 

Iron overload is a risk in PKD despite transfusion status and can result in complications, e.g., cardiac issues, bone deformities, and fractures. Routine screening with iron studies is necessary as it may reveal the presence of iron toxicity. The presence of hyperferritinemia may indicate the onset of iron overload. Magnetic resonance imaging (MRI) for hemosiderosis is useful in selected patients. Hemosiderosis (the accumulation of iron in the organs) requires iron-chelation therapy with deferoxamine.(2,4)

The management of chronic anemia requires supportive treatment. Of concern are states that are associated with increased folate demand, e.g., growth during childhood, pregnancy, and hemolytic crises. In these cases, folic acid supplementation is often warranted. Blood transfusions often help to alleviate anemia, but decisions for transfusion must take into account the risks and benefits.(2) 

Splenectomy is indicated for massive splenomegaly. This eliminates the risk of traumatic rupture. Severe anemia may also benefit from splenectomy. Total splenectomy is advocated in late childhood.(2) 

Current guidelines for PKD principally focus on supportive, rather than curative treatment of the disease. After a definitive diagnosis is established by qualitative and quantitative reduction in enzyme activity and a positive finding of homozygous or heterozygous gene mutations in the PKLR gene, patients are put into supportive care which constitutes the following framework:(3)

• Folic acid supplementation
  • Daily folic acid supplementation recommended in patients with moderate hemolysis, or with mild hemolysis coupled with a restricted diet to maintain effective erythropoiesis
• Red cell transfusions
  • These should be specified for each patient after a meticulous assessment of their tolerance regarding anemia, quality of life, and physical activity, rather than a measure of their absolute hemoglobin levels. Further assessment after each transfusion is also required
• Splenectomy is the definitive treatment in those who are severely anemic or receive regular transfusions and in those at risk of splenic rupture
  • Indicated between the age of 5 year to before adolescence

Efficacy

The efficacy of Pyrukynd was evaluated in ACTIVATE, a multinational, randomized, double-blind, placebo-controlled clinical study (NCT03548220) of 80 adults with PKD who were not regularly transfused, defined as having had no more than 4 transfusions in the 52-week period prior to treatment and no transfusion in the 3-month period prior to treatment. Patients were included if they had documented presence of at least 2 variant alleles in the pyruvate kinase liver and red blood cell (PKLR) gene, of which at least 1 was a missense variant and Hb less than or equal to 10g/dL. Patients who were homozygous for the c1436G > A (p.R479H) variant or had 2 non-missense variants (without the presence of another missense variant) in the PKLR gene were excluded because these patients did not achieve Hb response (change from baseline in Hb greater than or equal to 1.5 g/dL at great than 50% of assessments) in the dose-ranging study.(1)

Efficacy was based upon Hb response, defined as a greater than or equal to 1.5 g/dL increase in Hb from baseline sustained at 2 or more scheduled assessments (Weeks 16, 20, and 24) during the fixed dose period without transfusions. In ACTIVATE, the LS Mean change form baseline with Pyrukynd compared to placebo was -0.4 (standard error [SE] 0.1) for jaundice (scale: 0-4), -1.1 (SE 0.4) for tiredness (scale: 0-10), and -0.3 (SE 0.3) for shortness of breath (scale: 0-10), assessed with the daily Pyruvate Kinase Deficiency Diary (PKDD) where lower scores represent less sign/symptom severity.(1)

In ACTIVATE, the majority of Pyrukynd-treated patients experienced an increase in Hb, while the majority of patients in the placebo arm experienced a decrease in Hb as measured by average change from baseline at Weeks 16, 20, and 24. 40% of patients in the Pyrukynd arm met the Hb response rate and 0% of patients in the placebo arm met the Hb response rate (p-value less than 0.0001).(1)

The efficacy of Pyrukynd in patients with PK deficiency who were regularly transfused was evaluated in ACTIVATE-T, a multinational single-arm clinical trial (NCT03559699) of 27 adults with PK deficiency who had a minimum of 6 transfusion episodes in the 52-week period prior to informed consent. Patients were included if they had documented presence of at least 2 variant alleles in the PKLR gene, of which at least 1 was a missense variant. Patients who were homozygous for the c1436G > A (p.R479H) variant or had 2 non-missense variants (without the presence of another missense variant) in the PKLR gene were excluded.(1)

Efficacy was based on transfusion reduction response and was defined as greater than or equal to 33% reduction in the number of red blood cell (RBC) units transfused during the fixed dose period compared with the patient’s historical transfusion burden. 33% of patients (95% CI) met the transfusion reduction response endpoint and 22% (95% CI) of patients were transfusion free.(1)

Safety

Pyrukynd (mitapivat) has no known FDA labeled contraindications.(1)

1

Pyrukynd Prescribing Information. Agios Pharmaceuticals, Inc. February 2022.

2

Enegela OA, Anjum F. Pyruvate Kinase Deficiency. [Updated 2021 Dec 8]. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2022 Jan-. Available from: https://www.ncbi.nlm.nih.gov/books/NBK560581/

3

Iqbal A, Habiba U, Waseem R, Islam Z. Pyruvate kinase activator: A major breakthrough in the world of Hematology. Ann Med Surg (Lond). 2022 Sep 14;82:104631. doi: 10.1016/j.amsu.2022.104631. PMID: 36268365; PMCID: PMC9577647.

4

Al-Samkari, H., Van Beers, E. J., Kuo, K. H. M., Barcellini, W., Bianchi, P., Glenthøj, A., Del Mar Mañú Pereira, M., Van Wijk, R., Glader, B., & Grace, R. F. (2020). The variable manifestations of disease in pyruvate kinase deficiency and their management. Haematologica, 105(9), 2229–2239. https://doi.org/10.3324/haematol.2019.240846

Pyrukynd

mitapivat sulfate tab

20 MG ; 5 MG ; 50 MG

M ; N ; O ; Y

N

Pyrukynd taper pack

mitapivat sulfate tab therapy pack

5 MG ; 7 x 20 MG & 7 x 5 MG ; 7 x 50 MG & 7 x 20 MG

M ; N ; O ; Y

N

Pyrukynd

mitapivat sulfate tab

20 MG ; 5 MG ; 50 MG

56

Tablets

28

DAYS

Pyrukynd taper pack

Mitapivat Sulfate Tab Therapy Pack

5 MG

7

Tablets

365

DAYS

Pyrukynd taper pack

Mitapivat Sulfate Tab Therapy Pack

7 x 20 MG & 7 x 5 MG

14

Tablets

365

DAYS

Pyrukynd taper pack

Mitapivat Sulfate Tab Therapy Pack

7 x 50 MG & 7 x 20 MG

14

Tablets

365

DAYS

Pyrukynd

mitapivat sulfate tab

20 MG ; 5 MG ; 50 MG

Blue Partner ; Commercial ; GenPlus ; Health Insurance Marketplace ; NetResults A Series ; SourceRx

Pyrukynd taper pack

mitapivat sulfate tab therapy pack

5 MG ; 7 x 20 MG & 7 x 5 MG ; 7 x 50 MG & 7 x 20 MG

Blue Partner ; Commercial ; GenPlus ; Health Insurance Marketplace ; NetResults A Series ; SourceRx

Pyrukynd

mitapivat sulfate tab

20 MG ; 5 MG ; 50 MG

Blue Partner ; Commercial ; GenPlus ; Health Insurance Marketplace ; NetResults A Series ; SourceRx

Pyrukynd taper pack

Mitapivat Sulfate Tab Therapy Pack

7 x 50 MG & 7 x 20 MG

Blue Partner ; Commercial ; GenPlus ; Health Insurance Marketplace ; NetResults A Series ; SourceRx

Pyrukynd taper pack

Mitapivat Sulfate Tab Therapy Pack

7 x 20 MG & 7 x 5 MG

Blue Partner ; Commercial ; GenPlus ; Health Insurance Marketplace ; NetResults A Series ; SourceRx

Pyrukynd taper pack

Mitapivat Sulfate Tab Therapy Pack

5 MG

Blue Partner ; Commercial ; GenPlus ; Health Insurance Marketplace ; NetResults A Series ; SourceRx

Initial Evaluation

Target Agent(s) will be approved when ALL of the following are met:

1. The patient has a diagnosis of hemolytic anemia with pyruvate kinase deficiency (PKD) as confirmed by genetic testing showing a pathogenic PKLR gene mutation AND
2. The patient is NOT homozygous for the c.1436G > A (p.R479H) variant AND
3. The patient has at least 2 variant alleles in the PKLR gene, of which at least 1 is a missense variant AND
4. ONE of the following:
   1. The patient has a hemoglobin of less than or equal to 10g/dL OR
   2. The patient has had more than 4 red blood cell (RBC) transfusions in the past year AND
5. If the patient has an FDA labeled indication, then ONE of the following:
   1. The patient’s age is within FDA labeling for the requested indication for the requested agent OR
   2. There is support for using the requested agent for the patient’s age for the requested indication AND
6. The prescriber is a specialist in the area of the patient’s diagnosis (e.g., hematologist) or the prescriber has consulted with a specialist in the area of the patient’s diagnosis AND
7. The patient does NOT have any FDA labeled contraindications to the requested agent

Length of Approval:  6 months

NOTE: If Quantity Limit applies, please see Quantity Limit Criteria

Renewal Evaluation

Target Agent(s) will be approved when ALL of the following are met:

1. The patient has been previously approved for the requested agent through the plan’s Prior Authorization process [Note: patients not previously approved for the requested agent will require initial evaluation review] AND
2. The patient has had clinical benefit with the requested agent (e.g., hemoglobin has increased or is within normal range, decrease in red blood cell transfusion burden) AND
3. The prescriber is a specialist in the area of the patient’s diagnosis (e.g., hematologist) or the prescriber has consulted with a specialist in the area of the patient’s diagnosis AND
4. The patient does NOT have any FDA labeled contraindications to the requested agent

Length of Approval:  12 months

NOTE: If Quantity Limit applies, please see Quantity Limit Criteria

Quantity limit for the Target Agent(s) will be approved when ONE of the following is met:

1. The requested quantity (dose) does NOT exceed the program quantity limit OR
2. ALL of the following:
   1. The requested quantity (dose) exceeds the program quantity limit AND
   2. The requested quantity (dose) does NOT exceed the maximum FDA labeled dose for the requested indication AND
   3. The requested quantity (dose) cannot be achieved with a lower quantity of a higher strength that does NOT exceed the program quantity limit

Length of Approval:  Initial request 6 months  Renewal request 12 months