A Study of AG-348 in Adult Participants With Pyruvate Kinase (PK) Deficiency
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ClinicalTrials.gov Identifier: NCT02476916 |
Recruitment Status :
Active, not recruiting
First Posted : June 22, 2015
Results First Posted : June 11, 2020
Last Update Posted : June 13, 2022
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Condition or disease | Intervention/treatment | Phase |
---|---|---|
Pyruvate Kinase Deficiency | Drug: AG-348 | Phase 2 |
Study Type : | Interventional (Clinical Trial) |
Actual Enrollment : | 52 participants |
Allocation: | Randomized |
Intervention Model: | Parallel Assignment |
Masking: | None (Open Label) |
Primary Purpose: | Treatment |
Official Title: | A Phase 2, Open Label, Randomized, Dose Ranging, Safety, Efficacy, Pharmacokinetic and Pharmacodynamic Study of AG-348 in Adult Patients With Pyruvate Kinase Deficiency |
Actual Study Start Date : | June 26, 2015 |
Actual Primary Completion Date : | May 8, 2017 |
Estimated Study Completion Date : | May 2025 |

Arm | Intervention/treatment |
---|---|
Experimental: AG-348 50 mg BID
Participants with PK deficiency received AG-348, 50 milligrams (mg), as initial dose, twice daily (BID) for the Core Period (Week 24).
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Drug: AG-348
Participants with PK deficiency were randomized to either receive AG-348, 50 or 300 mg, as initial doses, BID for the Core Period (Week 24). At the Week 24 visit, Core Period participants who had safely tolerated AG-348 and demonstrated clinical activity in response to AG-348 were potentially eligible to immediately roll over to the Extension Period for continued treatment. Participants were assigned to initial doses, however, over the course of the core period were treated across a range of doses due to treatment emergent adverse events (AEs) and hemoglobin (Hb) levels exceeding mid-point of sex-adjusted ranges.
Other Name: Mitapivat |
Experimental: AG-348 300 mg BID
Participants with PK deficiency received AG-348, 300 mg, as initial dose, BID for the Core Period (Week 24).
|
Drug: AG-348
Participants with PK deficiency were randomized to either receive AG-348, 50 or 300 mg, as initial doses, BID for the Core Period (Week 24). At the Week 24 visit, Core Period participants who had safely tolerated AG-348 and demonstrated clinical activity in response to AG-348 were potentially eligible to immediately roll over to the Extension Period for continued treatment. Participants were assigned to initial doses, however, over the course of the core period were treated across a range of doses due to treatment emergent adverse events (AEs) and hemoglobin (Hb) levels exceeding mid-point of sex-adjusted ranges.
Other Name: Mitapivat |
- Percentage of Participants Experiencing at Least One Adverse Event (AEs) in the Core Period [ Time Frame: Up to Week 24 ]An AE was defined as any untoward medical occurrence associated with the use of a drug in humans, whether or not considered study drug-related.
- Change From Baseline in Hemoglobin (Hb) Value at Week 24 [ Time Frame: Baseline and Week 24 ]Change (absolute change) from baseline was calculated as post-baseline value - baseline value. Increased Hb values indicate improvement.
- Change From Baseline in Hematocrit at Week 24 [ Time Frame: Baseline and Week 24 ]Change (absolute change) from baseline was calculated as post-baseline value - baseline value. Increased hematocrit values indicate improvement.
- Change From Baseline in Reticulocyte Count at Week 24 [ Time Frame: Baseline and Week 24 ]Change (absolute change) from baseline was calculated as post-baseline value - baseline value. Decreased reticulocyte count values indicate improvement.
- Change From Baseline in Haptoglobin at Week 24 [ Time Frame: Baseline and Week 24 ]Change (absolute change) from baseline was calculated as post-baseline value - baseline value. Increased haptoglobin values indicate improvement.
- Change From Baseline in Carbon Monoxide at Week 24 [ Time Frame: Baseline and Week 24 ]Change (absolute change) from baseline was calculated as post-baseline value - baseline value. Decreased carbon monoxide values indicate improvement.
- Change From Baseline in Lactate Dehydrogenase (LDH) at Week 24 [ Time Frame: Baseline and Week 24 ]Change (absolute change) from baseline was calculated as post-baseline value - baseline value. Decreased LDH values indicate improvement.
- Change From Baseline in Total Bilirubin at Week 24 [ Time Frame: Baseline and Week 24 ]Change (absolute change) from baseline was calculated as post-baseline value - baseline value. Decreased total bilirubin values indicate improvement.
- Change From Baseline in Indirect Bilirubin at Week 24 [ Time Frame: Baseline and Week 24 ]Change (absolute change) from baseline was calculated as post-baseline value - baseline value. Decreased indirect bilirubin values indicate improvement.
- Change From Baseline in Erythropoietin (EPO) at Week 24 [ Time Frame: Baseline and Week 24 ]Change (absolute change) from baseline was calculated as post-baseline value - baseline value. Decreased EPO values indicate improvement.
- Change From Baseline in Hepcidin at Week 24 [ Time Frame: Baseline and Week 24 ]Change (absolute change) from baseline was calculated as post-baseline value - baseline value. Decreased hepcidin values indicate improvement.
- Change From Baseline in Ferritin at Week 24 [ Time Frame: Baseline and Week 24 ]Change (absolute change) from baseline was calculated as post-baseline value - baseline value. Decreased ferritin values indicate improvement.
- Change From Baseline in Transferrin Saturation at Week 24 [ Time Frame: Baseline and Week 24 ]Transferrin saturation is the ratio of serum iron to iron-binding capacity. Change (absolute change) from baseline was calculated as post-baseline value - baseline value. Decreased transferrin saturation values indicate improvement.
- Area Under the Concentration-time Curve From Time Zero to the Last Non-zero Concentration (AUC0-t) for AG-348 and Its Metabolite AGI-8702 [ Time Frame: pre-dose, 0.5, 1, 2, 4, 8, 12 hours post-dose Day 1 and pre-dose, 0.5, 1, 2, 4, 8 hours post-dose Day 15 ]Pre-dose pharmacokinetic concentrations, if any, were excluded from the pharmacokinetic analyses.
- Maximum Plasma Concentration (Cmax) for AG-348 and Its Metabolite AGI-8702 [ Time Frame: pre-dose, 0.5, 1, 2, 4, 8, 12 hours post-dose Day 1 and pre-dose, 0.5, 1, 2, 4, 8 hours post-dose Day 15 ]Pre-dose pharmacokinetic concentrations, if any, were excluded from the pharmacokinetic analyses.
- Time to Reach Peak Plasma Concentration (Tmax) for AG-348 and Its Metabolite AGI-8702 [ Time Frame: pre-dose, 0.5, 1, 2, 4, 8, 12 hours post-dose Day 1 and pre-dose, 0.5, 1, 2, 4, 8 hours post-dose Day 15 ]Pre-dose pharmacokinetic concentrations, if any, were excluded from the pharmacokinetic analyses.
- Apparent Clearance at Steady-State (Clss/F) for AG-348 and Its Metabolite AGI-8702 [ Time Frame: pre-dose, 0.5, 1, 2, 4, 8 hours post-dose Day 15 ]Pre-dose pharmacokinetic concentrations, if any, were excluded from the pharmacokinetic analyses.
- Maximum Change From Baseline Response Value Over 12 Hours Post-dose (BRmax) for Adenosine Triphosphate (ATP) [ Time Frame: pre-dose, 0.5, 1, 2, 4, 8, 12 hours post-dose Day 1 and pre-dose, 0.5, 1, 2, 4, 8 hours post-dose Day 15 ]Pre-dose concentration observed on Day 1 was used as Baseline for calculation of change from baseline.
- Maximum Change From Baseline Response Value Over 12 Hours Post-dose (BRmax) for 2,3 - Diphosphoglycerate (2,3-DPG) [ Time Frame: pre-dose, 0.5, 1, 2, 4, 8, 12 hours post-dose Day 1 and pre-dose, 0.5, 1, 2, 4, 8 hours post-dose Day 15 ]Pre-dose concentration observed on Day 1 was used as Baseline for calculation of change from baseline.

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.
Ages Eligible for Study: | 18 Years and older (Adult, Older Adult) |
Sexes Eligible for Study: | All |
Accepts Healthy Volunteers: | No |
Inclusion Criteria:
- Informed consent
- Male or female, aged 18 years and older
- Known medical history of PK deficiency
- PK deficiency confirmed by enzymatic assay at Screening
- Genotypic characterization of PKR gene at Screening
- Genotypic characterization of uridine-5'-diphosphate-glucuronyltransferase-A1 (UGTA1) gene to document underlying Gilbert's disease (Gilbert's disease patients are eligible)
- Males Hb ≤ 12.0 g/dL, females Hb ≤ 11 g/dL
- Transfusion independent, defined as no more than 3 units of red blood cells (RBC) transfused in 12 months prior to the first day of study dosing and no transfusions within 4 months of first day of study dosing
- Splenectomized patients must have had the procedure at least 6 months prior to Screening and must be up-to-date in recommended vaccinations
- Eastern Cooperative Oncology Group (ECOG) performance status ≤ 2
- Must be taking at least 1 mg folic acid daily in the 21 days prior to screening
- Adequate organ function defined by liver function, kidney function, platelet count and coagulation assessments
- Agreement to use approved contraceptive measures
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Women must not be breastfeeding
For entry into the Extension Period, patients must meet criteria # 15-16:
- Must have completed 24 weeks of treatment during the Core Period and tolerated AG-348
- The treating Investigator agrees that there is a potential for clinical benefit to continued treatment and recommends participation in the Extension Period and the Medical Monitor approves
Exclusion criteria
- Hb ˃ 12.0 g/dL if male, Hb ˃11.0 g/dL if female
- Additional diagnosis of other congenital or acquired blood disorder
- Iron overload sufficiently severe to result in cardiac, hepatic or pancreatic insufficiency
- Bone marrow or stem cell transplant
- Clinically symptomatic cholelithiasis or cholecystitis
- Currently enrolled in any other investigational trial. Participation in the PK Deficiency Natural History Study (NCT02053480) is permitted
- Exposure to any investigational drug, device or procedure within 28 days prior to screening or during trial participation
- Concurrent medical condition such as poorly controlled hypertension, heart failure, active infection, frequent post-splenectomy sepsis, Hepatitis B or C, Human Immunodeficiency Virus type 1 (HIV1) or Human Immunodeficiency Virus type 2 (HIV2) infection, poorly controlled diabetes mellitus, history of primary malignancy with the exception of curatively treated nonmelanomatous skin cancer, cervical cancer of breast cancer in situ
- Major surgery in the last 6 months
- Psychiatric disorder that could compromise the ability of the patient to cooperate with the study
- Serum bilirubin higher to the upper limit of normal attributable to factors other than hemolysis or Gilbert's Syndrome
- Use of restricted products known to strongly inhibit cytochrome P450 (CYP) 3A4 metabolism within 5 days prior to Prior Day 1 dosing, or to strongly induce cytochrome P450 3A4 (CYP3A4) metabolism within 28 days prior to Day 1 dosing, or to strongly inhibit P-glycoprotein transporter within 5 days prior to Day 1 dosing, or digoxin within 5 days prior to Day 1 dosing.
- Heart-rate corrected QT interval - Fridericia's method (QTcF) interval ˃ 450 ms in male, QTcF > 470 ms in female, with the exception of patients with a left Bundle Branch Block
- Cardiac arrhythmias that are clinically significant or treated with drugs that are substrates of CYP3A4
- Allergy to sulfonamides if characterized by acute hemolytic anemia, anaphylaxis, rash of erythema multiforme type or Stevens-Johnson Syndrome
- Any other medical or psychological condition deemed by the Investigator to be likely to interfere with a patient's ability to participate in the study
- Patients will not be permitted to enter the Extension Period if: The patient experienced AEs during the Core Period that are considered by the treating Investigator or the Sponsor's designated Medical Monitor to pose a significant safety risk to the patient if treatment were to be extended

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.
Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT02476916
United States, California | |
Stanford University | |
Palo Alto, California, United States, 94304 | |
United States, Massachusetts | |
Boston Children's Hospital | |
Boston, Massachusetts, United States, 02215 | |
United States, Michigan | |
Wayne State University School of Medicine - Children's Hospital of Michigan | |
Detroit, Michigan, United States, 48201 | |
United States, New York | |
New York Presbyterian Hospital- Weil Cornell Medical College | |
New York, New York, United States, 10065 | |
United States, Pennsylvania | |
Central Pennsylvania Clinic | |
Belleville, Pennsylvania, United States, 17004 | |
Children Hospital of Philadelphia (CHOP) | |
Philadelphia, Pennsylvania, United States, 19104 | |
United States, Utah | |
University of Utah | |
Salt Lake City, Utah, United States, 84113 | |
Canada, Ontario | |
University Health Network | |
Toronto, Ontario, Canada, M5G 2C4 | |
France | |
Hôpital Henri Mondor | |
Créteil, Ile-de-France, France, 94010 | |
Hôpital Saint-Vincent de Paul | |
Lille, Nord, France, 59000 | |
Italy | |
UOC Oncoematologia Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico | |
Milano, Italy, 20122 | |
Netherlands | |
Universitair Medisch Centrum Utrecht | |
Utrecht, Netherlands, 3584 CX | |
United Kingdom | |
Hammersmith Hospital | |
London, United Kingdom, W12 0NN |
Documents provided by Agios Pharmaceuticals, Inc.:
Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):
Responsible Party: | Agios Pharmaceuticals, Inc. |
ClinicalTrials.gov Identifier: | NCT02476916 |
Other Study ID Numbers: |
AG348-C-003 2015-000484-13 ( EudraCT Number ) |
First Posted: | June 22, 2015 Key Record Dates |
Results First Posted: | June 11, 2020 |
Last Update Posted: | June 13, 2022 |
Last Verified: | June 2022 |
Individual Participant Data (IPD) Sharing Statement: | |
Plan to Share IPD: | No |
Studies a U.S. FDA-regulated Drug Product: | Yes |
Studies a U.S. FDA-regulated Device Product: | No |
Pyruvate Kinase Deficiency Hemolytic anemia Pyruvate Kinase Isoform R (PKR) Drive PK |
Anemia, Hemolytic, Congenital Nonspherocytic Pyruvate Metabolism, Inborn Errors Anemia, Hemolytic, Congenital Anemia, Hemolytic Anemia |
Hematologic Diseases Genetic Diseases, Inborn Carbohydrate Metabolism, Inborn Errors Metabolism, Inborn Errors Metabolic Diseases |