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ph-91175

Pyrukynd (mitapivat) Prior Authorization with Quantity Limit Program Summary

Policy Number: PH-91175

This program applies to Blue Partner, Commercial, GenPlus, NetResults A series, SourceRx and Health Insurance Marketplace formularies.

POLICY REVIEW CYCLE

Effective Date	Date of Origin
01-01-2025

FDA LABELED INDICATIONS AND DOSAGE

Agent(s)	FDA Indication(s)	Notes	Ref#
Pyrukynd® (mitapivat) Tablet	Treatment of hemolytic anemia in adults with pyruvate kinase (PK) deficiency		1

Agent(s)

FDA Indication(s)

Notes

Ref#

Pyrukynd®

(mitapivat)

Tablet

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

See package insert for FDA prescribing information: https://dailymed.nlm.nih.gov/dailymed/index.cfm

CLINICAL RATIONALE

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) It is recommended that for those who have an initial diagnosis determined by pyruvate kinase enzyme activity measurements, a confirmatory diagnosis be obtained through PKLR gene molecular analysis. And for those who have an initial diagnosis assessed by PKLR gene molecular analysis, if the patient does not have two known pathogenic mutations in PKLR, a confirmatory diagnosis should be obtained through pyruvate kinase enzyme activity measurement. (5) 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

Pyrukynd is recommended in adult patients with pyruvate kinase deficiency who are anemic, and who don't have two non-missense mutations, regardless of transfusion or splenectomy status.(5) Pyrukynd therapy should be discontinued is the patient who are not receiving a clinical response after 3-6 months, depending on if the patient is receiving transfusions. Patients who do not achieve at least a 33% reduction in transfusion requirement after optimizing Pyrukynd therapy should discontinue therapy unless the patient is achieving marked improvement in other key disease parameters such as iron status, jaundice, and patient reported health outcomes.(5)

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)

REFERENCES

Number	Reference
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
5	Al-Samkari, H., Shehata, N., Lang-Robertson, K., Bianchi, P., Glenthøj, A., Sheth, S., Neufeld, E. J., Rees, D. C., Chonat, S., Kuo, K. H. M., Rothman, J. A., Barcellini, W., Van Beers, E. J., Pospísilová, D., Shah, A. J., Van Wijk, R., Glader, B., Del Mar Mañú Pereira, M., Andres, O., . . . Grace, R. F. (2024). Diagnosis and management of pyruvate kinase deficiency: international expert guidelines. the Lancet. Haematology, 11(3), e228-e239. https://doi.org/10.1016/s2352-3026(23)00377-0

POLICY AGENT SUMMARY PRIOR AUTHORIZATION

Target Brand Agent(s)	Target Generic Agent(s)	Strength	Targeted MSC	Available MSC	Final Age Limit	Preferred Status

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

POLICY AGENT SUMMARY QUANTITY LIMIT

Target Brand Agent Name(s)	Target Generic Agent Name(s)	Strength	QL Amount	Dose Form	Day Supply	Duration	Addtl QL Info	Allowed Exceptions	Targeted NDCs When Exclusions Exist

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

CLIENT SUMMARY – PRIOR AUTHORIZATION

Target Brand Agent Name(s)	Target Generic Agent Name(s)	Strength	Client Formulary
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

CLIENT SUMMARY – QUANTITY LIMITS

Target Brand Agent Name(s)	Target Generic Agent Name(s)	Strength	Client Formulary
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	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	7 x 50 MG & 7 x 20 MG	Blue Partner ; Commercial ; GenPlus ; Health Insurance Marketplace ; NetResults A Series ; SourceRx

PRIOR AUTHORIZATION CLINICAL CRITERIA FOR APPROVAL

Module	Clinical Criteria for Approval
	Initial Evaluation Target Agent(s) will be approved when ALL of the following are met: The patient has a diagnosis of hemolytic anemia with pyruvate kinase deficiency (PKD) AND ONE of the following: Genetic testing showing a pathogenic PKLR gene mutation OR The patient does NOT have two known pathogenic mutations in the PKLR gene, AND the patient has a decrease in pyruvate kinase enzyme activity AND The patient is NOT homozygous for the c.1436G > A (p.R479H) variant AND The patient has at least 2 variant alleles in the PKLR gene, of which at least 1 is a missense variant AND The patient does NOT have two non-missense mutations AND If the patient has an FDA labeled indication, then ONE of the following: The patient’s age is within FDA labeling for the requested indication for the requested agent OR There is support for using the requested agent for the patient’s age for the requested indication AND 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 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: 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 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 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 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

Module

Clinical Criteria for Approval

Initial Evaluation

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

The patient has a diagnosis of hemolytic anemia with pyruvate kinase deficiency (PKD) AND ONE of the following:
1. Genetic testing showing a pathogenic PKLR gene mutation OR
2. The patient does NOT have two known pathogenic mutations in the PKLR gene, AND the patient has a decrease in pyruvate kinase enzyme activity AND
The patient is NOT homozygous for the c.1436G > A (p.R479H) variant AND
The patient has at least 2 variant alleles in the PKLR gene, of which at least 1 is a missense variant AND
The patient does NOT have two non-missense mutations AND
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
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
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:

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
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
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
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 CLINICAL CRITERIA FOR APPROVAL

Module	Clinical Criteria for Approval
	Quantity limit for the Target Agent(s) will be approved when ONE of the following is met: The requested quantity (dose) does NOT exceed the program quantity limit OR The requested quantity (dose) exceeds the program quantity limit AND ONE of the following: BOTH of the following: The requested agent does NOT have a maximum FDA labeled dose for the requested indication AND There is support for therapy with a higher dose for the requested indication OR BOTH of the following: The requested quantity (dose) does NOT exceed the maximum FDA labeled dose for the requested indication AND There is support for why 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: up to 12 months

Module

Clinical Criteria for Approval

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

The requested quantity (dose) does NOT exceed the program quantity limit OR
The requested quantity (dose) exceeds the program quantity limit AND ONE of the following:
1. BOTH of the following:
  1. The requested agent does NOT have a maximum FDA labeled dose for the requested indication AND
  2. There is support for therapy with a higher dose for the requested indication OR
2. BOTH of the following:
  1. The requested quantity (dose) does NOT exceed the maximum FDA labeled dose for the requested indication AND
  2. There is support for why 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: up to 12 months

This pharmacy policy is not an authorization, certification, explanation of benefits or a contract. Eligibility and benefits are determined on a case-by-case basis according to the terms of the member’s plan in effect as of the date services are rendered. All pharmacy policies are based on (i) information in FDA approved package inserts (and black box warning, alerts, or other information disseminated by the FDA as applicable); (ii) research of current medical and pharmacy literature; and/or (iii) review of common medical practices in the treatment and diagnosis of disease as of the date hereof. Physicians and other providers are solely responsible for all aspects of medical care and treatment, including the type, quality, and levels of care and treatment.

The purpose of Blue Cross and Blue Shield of Alabama’s pharmacy policies are to provide a guide to coverage. Pharmacy policies are not intended to dictate to physicians how to practice medicine. Physicians should exercise their medical judgment in providing the care they feel is most appropriate for their patients.

Neither this policy, nor the successful adjudication of a pharmacy claim, is guarantee of payment.

Commercial _ PS _ Pyrukynd_PAQL _ProgSum_ 01-01-2025