Clinical trial NCT03559699: A Study Evaluating the Efficacy and Safety of AG-348 in Regularly Transfused Adult Participants With Pyruvate Kinase Deficiency (PKD)
Official title: An Open-Label Study To Evaluate the Efficacy and Safety of AG-348 in Regularly Transfused Adult Subjects With Pyruvate Kinase (PK) Deficiency
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE3
Conditions: Pyruvate Kinase Deficiency
Anemia, Hemolytic
Lead sponsor: Agios Pharmaceuticals, Inc.
Sponsor class: INDUSTRY
First posted: 2018-06-18
Enrollment: 27
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

Brief summary: Study AG348-C-007 was a multicenter study designed to evaluate the efficacy and safety of treatment with AG-348 in a minimum of 20, with up to 40, participants with pyruvate kinase (PK) deficiency, who were regularly receiving blood transfusions. The study was composed of two parts. During Part 1, Dose Optimization Period, participants started on a dose of 5 mg AG-348 administered twice daily. Over the course of Part 1 each participant's dose of AG-348 was sequentially increased to 20 mg twice a day, followed by 50 mg twice a day depending on their tolerance. During Part 2, Fixed-Dose Period, participants received AG-348 at their optimized dose from Part 1.


Eligibility criteria: Inclusion Criteria:

* Informed consent;
* Male or female, aged 18 or older;
* Presence of at least 2 mutant alleles in the Pyruvate Kinase Liver and RBC (PKLR) gene, of which at least 1 is a missense mutation;
* History of a minimum of 6 transfusion episodes in the 52-week period prior to date of informed consent;
* Complete records of transfusion history for the 52 weeks prior to the date of informed consent, including all transfusion dates, number of blood units transfused for all the transfusions, and Hb concentrations within 1 week prior to transfusion for at least 80% of the transfusions;
* Have received at least 0.8 mg of oral folic acid daily for at least 21 days prior to the first dose of study drug, to be continued daily during study participation;
* Have adequate organ function;
* Negative serum pregnancy test for women of reproductive potential;
* For women of reproductive potential as well as fertile men and their partners who are women of reproductive potential: be abstinent or agree to use 2 forms of contraception, 1 of which must be considered highly effective, from the time of giving informed consent, during the study, and for 28 days following the last dose of AG-348;
* Willing to comply with all study procedures, in particular the individual transfusion trigger (TT) calculated based on 52 weeks of transfusion history, for the duration of the study.

Exclusion Criteria:

* Homozygous for the R479H mutation or have 2 non-missense mutations, without the presence of another missense mutation, in the PKLR gene;
* Significant medical condition that confers an unacceptable risk to participate in the study, and/or that could confound the interpretation of the study data;
* History of transfusions occurring on average more frequently than once every 3 weeks during the 52 weeks prior to date of informed consent;
* Splenectomy scheduled during the study treatment period or have undergone splenectomy within 12 months prior to signing informed consent;
* Currently enrolled in another therapeutic clinical trial. Prior participation in the PK Deficiency Natural History Study (NHS) (NCT02053480) or PK Deficiency Registry is permitted;
* Exposure to any investigational drug, device, or procedure within 3 months prior to the first dose of study drug;
* Prior bone marrow or stem cell transplant;
* Currently pregnant or breastfeeding;
* History of major surgery within 6 months of signing informed consent;
* Currently receiving medications that are strong inhibitors of CYP3A4, strong inducers of CYP3A4, strong inhibitors of P-glycoprotein (P-gp), or digoxin (a P-gp sensitive substrate medication) that have not been stopped for a duration of at least 5 days or 5 times their half-lives (whichever is longer) prior to start of study drug;
* Currently receiving hematopoietic stimulating agents (eg, erythropoietins \[EPOs\], granulocyte colony stimulating factors, thrombopoietins) that have not been stopped for a duration of at least 28 days prior to the first dose of study drug;
* History of allergy to sulfonamides if characterized by acute hemolytic anemia, drug induced liver injury, anaphylaxis, rash of erythema multiforme type or Stevens-Johnson syndrome, cholestatic hepatitis or other serious clinical manifestations;
* Allergy to AG-348 or its excipients;
* Currently receiving anabolic steroids, including testosterone preparations, within 28 days prior to the first dose of study drug.

Primary outcomes:
measure: Percentage of Participants Achieving a Reduction in Transfusion Burden in Part 2
timeFrame: From Part 2, Day 1 to Part 2 Week 24
Secondary outcomes:
measure: Annualized Number of RBC Units Transfused During the Study
timeFrame: Part 1 Day 1 to Part 2 Week 24
measure: Number of Transfusion Episodes in Part 2
timeFrame: From Part 2 Day 1 to Part 2 Week 24
measure: Percentage of Transfusion-Free Participants in Part 2
timeFrame: From Part 2 Day 1 to Part 2 Week 24
measure: Percentage of Participants Achieving Normal Hemoglobin (Hb) Concentrations in Part 2
timeFrame: From Part 2 Day 1 to Part 2 Week 24
measure: Percentage of Participants With Adverse Events
timeFrame: Through 4 weeks after last dose (approximately Part 2, Week 31)
Other outcomes:
measure: Percentage of Participants Experiencing an Adverse Event of Special Interest (AESI)
timeFrame: From Part 1 Day 1 to end of Part 2, including follow-up (Day 197)
measure: Bone Mineral Density Z-Score
timeFrame: Part 1, Day 1, Part 2, Day 1 and Part 2, Week 24
measure: Bone Mineral Density T-Score
timeFrame: Part 1, Day 1, Part 2, Day 1 and Part 2, Week 24
Locations:
city: Oakland
country: United States
facility: UCSF Benioff Children's Hospital
state: California
city: Atlanta
country: United States
facility: Emory University
state: Georgia
city: Boston
country: United States
facility: Massachusetts General Hospital
state: Massachusetts
city: Seattle
country: United States
facility: Seattle Cancer Care Alliance
state: Washington
city: Toronto
country: Canada
facility: Toronto General Hospital, University Health Network
city: Herlev
country: Denmark
facility: University of Copenhagen, Herlev Hospital
city: Créteil
country: France
facility: Hopital Universitaire Henri Mondor
city: Marseille, Cedex 5
country: France
facility: Hôpital de la Timone
city: Dublin
country: Ireland
facility: St James's Hospital Department of Haematology
city: Milano
country: Italy
facility: Fondazione IRCCS Ca' Granda, Ospedale Maggiore Policlinico
city: Napoli
country: Italy
facility: AORN Cardarelli
city: Napoli
country: Italy
facility: Ospedale Galliera
city: Napoli
country: Italy
facility: AOU Policlinico, Università della Campania "Luigi Vanvitelli"
city: Utrecht
country: Netherlands
facility: Universitair Medisch Centrum Utrecht
city: Bangkok
country: Thailand
facility: Department of Paediatrics and Thalassaemia Center, Faculty of Medicine Siriraj Hospital, Mahidol University
city: Cambridge
country: United Kingdom
facility: Addenbrooke's Hospital
city: London
country: United Kingdom
facility: Imperial College Healthcare NHS Trust, Hammersmith Hospital
city: London
country: United Kingdom
facility: University College London
city: Manchester
country: United Kingdom
facility: Manchester Royal Infirmary
Study officials:
affiliation: Agios Pharmaceuticals, Inc.
name: Medical Affairs
role: STUDY_CHAIR
References:
citation: Glenthoj A, van Beers EJ, Al-Samkari H, Viprakasit V, Kuo KHM, Galacteros F, Chonat S, Porter J, Zagadailov E, Xu R, Oluyadi A, Hawkins P, Gheuens S, Beynon V, Barcellini W; ACTIVATE-T investigators. Mitapivat in adult patients with pyruvate kinase deficiency receiving regular transfusions (ACTIVATE-T): a multicentre, open-label, single-arm, phase 3 trial. Lancet Haematol. 2022 Oct;9(10):e724-e732. doi: 10.1016/S2352-3026(22)00214-9. Epub 2022 Aug 18.
citation: Rab MAE, Van Oirschot BA, Kosinski PA, Hixon J, Johnson K, Chubukov V, Dang L, Pasterkamp G, Van Straaten S, Van Solinge WW, Van Beers EJ, Kung C, Van Wijk R. AG-348 (Mitapivat), an allosteric activator of red blood cell pyruvate kinase, increases enzymatic activity, protein stability, and ATP levels over a broad range of PKLR genotypes. Haematologica. 2021 Jan 1;106(1):238-249. doi: 10.3324/haematol.2019.238865.