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Pyrukynd (mitapivat) Prior Authorization with Quantity Limit Program Summary
Policy Number: PH-1175
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 |
07-01-2024 |
|
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 |
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) 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)
|
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 |
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 |
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 |
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:
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:
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:
Length of Approval: Initial request 6 months Renewal request 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_ 07-01-2024