Mitapivat

Mitapivat
Clinical data
Trade names	Pyrukynd
Other names	AG-348, Mitapivat sulfate (USAN US)
License data	US DailyMed: Mitapivat;
Routes of; administration	By mouth
ATC code	B06AX04 (WHO) ;
Legal status
Legal status	US: ℞-only; EU: Rx-only;
Identifiers
CAS Number	1260075-17-9;
PubChem CID	59634741;
IUPHAR/BPS	10473;
DrugBank	DB16236; as salt: DBSALT003215;
ChemSpider	29763395;
UNII	2WTV10SIKH; as salt: N4JTA67V3O;
KEGG	as salt: D11408;
ChEMBL	ChEMBL4299940; as salt: ChEMBL4297223;
Chemical and physical data
Formula	C24H26N4O3S
Molar mass	450.56 g·mol−1
3D model (JSmol)	Interactive image;
	SMILES O=C(N1CCN(CC2CC2)CC1)C1=CC=C(NS(=O)(=O)C2=CC=CC3=C2N=CC=C3)C=C1;
	InChI InChI=1S/C24H26N4O3S/c29-24(28-15-13-27(14-16-28)17-18-6-7-18)20-8-10-21(11-9-20)26-32(30,31)22-5-1-3-19-4-2-12-25-23(19)22/h1-5,8-12,18,26H,6-7,13-17H2; Key:XAYGBKHKBBXDAK-UHFFFAOYSA-N;

Mitapivat, sold under the brand name Pyrukynd, is a medication used to treat hemolytic anemia.^[1] It is taken as the sulfate hydrate salt by mouth.^[1] Mitapivat is a pyruvate kinase activator.^[1]

The most common side effects include decreases in estrone and estradiol (types of the estrogen hormone) in men, increased urate (a type of salt in the body), back pain, and joint stiffness.^[3]

Mitapivat was approved for medical use in the United States in February 2022,^[1]^[3]^[4]^[5] and in the European Union in November 2022.^[2] The US Food and Drug Administration (FDA) considers it to be a first-in-class medication.^[6]^[7]

Medical uses

Mitapivat is indicated for the treatment of hemolytic anemia in adults with pyruvate kinase deficiency.^[1]^[5]

Pharmacology

Mechanism of action

Mitapivat binds to and activates pyruvate kinase, thereby enhancing glycolytic pathway activity, improving adenosine triphosphate (ATP) levels and reducing 2,3-diphosphoglycerate (2,3-DPG) levels.^[8] Mutations in pyruvate kinase cause deficiency in pyruvate kinase which prevents adequate red blood cell (RBC) glycolysis, leading to a buildup of the upstream glycolytic intermediate 2,3-DPG and deficiency in the pyruvate kinase product ATP.^[8]^[9]

History

The FDA approved mitapivat based on evidence from two clinical trials of 107 participants with pyruvate kinase deficiency.^[3] Trial 1 (NCT03548220) of 80 adults with pyruvate kinase deficiency who did not receive regular blood transfusions and trial 2 (NCT03559699) of 27 adults with pyruvate kinase deficiency who received regular blood transfusions.^[3] In trial 1, participants were randomly assigned to receive either mitapivat or a matched placebo tablet for an average duration of about 24 weeks. Neither the participants nor the healthcare providers knew which treatment was being given during the trial.^[3] Trial 1 was conducted at 36 sites in the following countries: Brazil, Canada, Denmark, France, Germany, Italy, Japan, Republic of Korea, Netherlands, Spain, Switzerland, Turkey, United Kingdom, and the United States.^[3] In Trial 2, all participants received mitapivat for an average duration of about 40 weeks.^[3] Trial 2 was conducted at 17 sites in the following countries: Canada, Denmark, France, Ireland, Italy, Netherlands, Thailand, United Kingdom, and the United States.^[3]

Society and culture

Legal status

On 15 September 2022, the Committee for Medicinal Products for Human Use (CHMP) of the European Medicines Agency (EMA) adopted a positive opinion, recommending the granting of a marketing authorization for the medicinal product Pyrukynd, intended for the treatment of an inherited condition called pyruvate kinase deficiency.^[10] The applicant for this medicinal product is Agios Netherlands B.V.^[10] Mitapivat was approved for medical use in the European Union in November 2022.^[2]^[11]

Names

Mitapivat is the international nonproprietary name (INN).^[12]

References

^ ^a ^b ^c ^d ^e ^f "Pyrukynd- mitapivat tablet, film coated Pyrukynd- mitapivat kit". DailyMed. 23 February 2022. Archived from the original on 3 March 2022. Retrieved 3 March 2022.
^ ^a ^b ^c "Pyrukynd EPAR". European Medicines Agency (EMA). 14 September 2022. Retrieved 5 December 2022. Text was copied from this source which is copyright European Medicines Agency. Reproduction is authorized provided the source is acknowledged.
^ ^a ^b ^c ^d ^e ^f ^g ^h "Drug Trials Snapshot: Pyrukynd". U.S. Food and Drug Administration (FDA). 1 June 2023. Retrieved 1 June 2023. This article incorporates text from this source, which is in the public domain.
^ "Agios Announces FDA Approval of Pyrukynd (mitapivat) as First Disease-Modifying Therapy for Hemolytic Anemia in Adults with Pyruvate Kinase Deficiency" (Press release). Agios Pharmaceuticals. 17 February 2022. Archived from the original on 20 February 2022. Retrieved 19 February 2022 – via GlobeNewswire.
^ ^a ^b Gormley N. "Pyrukynd (mitapivat) tablets NDA approval" (PDF). Center for Drug Evaluation and Research. Letter to Christina Baladi (Agios Pharmaceuticals, Inc.). U.S. Food and Drug Administration.
^ "Advancing Health Through Innovation: New Drug Therapy Approvals 2022". U.S. Food and Drug Administration (FDA). 10 January 2023. Retrieved 22 January 2023. This article incorporates text from this source, which is in the public domain.
^ New Drug Therapy Approvals 2022 (PDF). U.S. Food and Drug Administration (FDA) (Report). January 2024. Archived from the original on 14 January 2024. Retrieved 14 January 2024. This article incorporates text from this source, which is in the public domain.
^ ^a ^b "Mitapivat (Code C157039)". NCI Thesaurus. 31 January 2022. Archived from the original on 20 February 2022. Retrieved 19 February 2022. This article incorporates text from this source, which is in the public domain.
^ "PK-R allosteric activator AG-348". NCI Drug Dictionary. National Cancer Institute. Archived from the original on 10 August 2019. Retrieved 19 February 2022. This article incorporates text from this source, which is in the public domain.
^ ^a ^b "Pyrukynd: Pending EC decision". European Medicines Agency (EMA). 15 September 2022. Archived from the original on 19 September 2022. Retrieved 18 September 2022. Text was copied from this source which is copyright European Medicines Agency. Reproduction is authorized provided the source is acknowledged.
^ "Pyrukynd Product information". Union Register of medicinal products. Retrieved 3 March 2023.
^ World Health Organization (2017). "International nonproprietary names for pharmaceutical substances (INN): recommended INN: list 78". WHO Drug Information. 31 (3): 539. hdl:10665/330961.

External links

"Mitapivat sulfate". Drug Information Portal. U.S. National Library of Medicine.
Clinical trial number NCT03548220 for "A Study to Evaluate Efficacy and Safety of AG-348 in Not Regularly Transfused Adult Participants With Pyruvate Kinase Deficiency (PKD)" at ClinicalTrials.gov
Clinical trial number NCT03559699 for "A Study Evaluating the Efficacy and Safety of AG-348 in Regularly Transfused Adult Participants With Pyruvate Kinase Deficiency (PKD)" at ClinicalTrials.gov

[Pyrukynd_FDA_label-1] ^ ^a ^b ^c ^d ^e ^f "Pyrukynd- mitapivat tablet, film coated Pyrukynd- mitapivat kit". DailyMed. 23 February 2022. Archived from the original on 3 March 2022. Retrieved 3 March 2022.

[Pyrukynd_EPAR-2] "Pyrukynd EPAR". European Medicines Agency (EMA). 14 September 2022. Retrieved 5 December 2022. Text was copied from this source which is copyright European Medicines Agency. Reproduction is authorized provided the source is acknowledged.

[Drug_Trials_Snapshot:_Pyrukynd-3] ^ ^a ^b ^c ^d ^e ^f ^g ^h "Drug Trials Snapshot: Pyrukynd". U.S. Food and Drug Administration (FDA). 1 June 2023. Retrieved 1 June 2023. This article incorporates text from this source, which is in the public domain.

[Agios_PR-4] "Agios Announces FDA Approval of Pyrukynd (mitapivat) as First Disease-Modifying Therapy for Hemolytic Anemia in Adults with Pyruvate Kinase Deficiency" (Press release). Agios Pharmaceuticals. 17 February 2022. Archived from the original on 20 February 2022. Retrieved 19 February 2022 – via GlobeNewswire.

[FDA_approval_letter-5] Gormley N. "Pyrukynd (mitapivat) tablets NDA approval" (PDF). Center for Drug Evaluation and Research. Letter to Christina Baladi (Agios Pharmaceuticals, Inc.). U.S. Food and Drug Administration.

[New_Drug_Therapy_Approvals_2022-6] "Advancing Health Through Innovation: New Drug Therapy Approvals 2022". U.S. Food and Drug Administration (FDA). 10 January 2023. Retrieved 22 January 2023. This article incorporates text from this source, which is in the public domain.

[7] New Drug Therapy Approvals 2022 (PDF). U.S. Food and Drug Administration (FDA) (Report). January 2024. Archived from the original on 14 January 2024. Retrieved 14 January 2024. This article incorporates text from this source, which is in the public domain.

[NCI_C157039-8] "Mitapivat (Code C157039)". NCI Thesaurus. 31 January 2022. Archived from the original on 20 February 2022. Retrieved 19 February 2022. This article incorporates text from this source, which is in the public domain.

[9] "PK-R allosteric activator AG-348". NCI Drug Dictionary. National Cancer Institute. Archived from the original on 10 August 2019. Retrieved 19 February 2022. This article incorporates text from this source, which is in the public domain.

[Pyrukynd:_Pending_EC_decision-10] "Pyrukynd: Pending EC decision". European Medicines Agency (EMA). 15 September 2022. Archived from the original on 19 September 2022. Retrieved 18 September 2022. Text was copied from this source which is copyright European Medicines Agency. Reproduction is authorized provided the source is acknowledged.

[11] "Pyrukynd Product information". Union Register of medicinal products. Retrieved 3 March 2023.

[WHORecList78-12] World Health Organization (2017). "International nonproprietary names for pharmaceutical substances (INN): recommended INN: list 78". WHO Drug Information. 31 (3): 539. hdl:10665/330961.

[1]

[2]

[3]

[4]

[5]

[6]

[7]

[8]

[9]

[10]

[11]

[12]