A Study of AG-348 in Adult Participants With Pyruvate Kinase (PK) Deficiency

Study Overview
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Brief Summary
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Study AG348-C-003 is a multicenter study designed to evaluate the safety and efficacy of different dose levels of AG-348 (mitapivat) in participants with PK deficiency.

Detailed Description
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This is a Phase 2, open label, two arm, multicenter, randomized, dose-ranging study during which adult participants with PK deficiency will receive multiple doses of AG-348 for up to 24 weeks (Core Period); eligible participants may enter an Extension Period to receive AG-348 for up to 8 additional years. Data will be reviewed on a regular basis and study design, dose and schedule will be adapted based on these reviews. The study will evaluate the safety and tolerability of multiple doses of AG-348, pharmacokinetic and pharmacodynamic (PD) profile of AG-348 and early indicators of clinical efficacy.

Official Title
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A Phase 2, Open Label, Randomized, Dose Ranging, Safety, Efficacy, Pharmacokinetic and Pharmacodynamic Study of AG-348 in Adult Patients With Pyruvate Kinase Deficiency

Conditions
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Pyruvate Kinase Deficiency

Intervention / Treatment
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* Drug: AG-348


Participation Criteria
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Eligibility Criteria
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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 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

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: AG-348 50 mg BID<br>Participants with PK deficiency received AG-348, 50 milligrams (mg), as initial dose, twice daily (BID) for the Core Period (Week 24). | Drug: AG-348<br>* 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.<br>* Other names: Mitapivat;|
| Experimental: AG-348 300 mg BID<br>Participants with PK deficiency received AG-348, 300 mg, as initial dose, BID for the Core Period (Week 24). | Drug: AG-348<br>* 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.<br>* Other names: Mitapivat;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of Participants Experiencing at Least One Adverse Event (AEs) in the Core Period | 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. | Up to Week 24 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of Participants Experiencing at Least One AE Over the Duration of the Extension Period | 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. | Up to approximately 8.5 years | 
| Change From Baseline in Hemoglobin (Hb) Value at Week 24 | Change (absolute change) from baseline was calculated as post-baseline value - baseline value. Increased Hb values indicate improvement. | Baseline and Week 24 | 
| Change From Baseline in Hb Value Over the Duration of the Extension Period | Change (absolute change) from baseline will be calculated as post-baseline value - baseline value. Increased Hb values indicate improvement. | Up to approximately 8.5 years | 
| Change From Baseline in Hematocrit at Week 24 | Change (absolute change) from baseline was calculated as post-baseline value - baseline value. Increased hematocrit values indicate improvement. | Baseline and Week 24 | 
| Change From Baseline in Hematocrit Over the Duration of the Extension Period | Change (absolute change) from baseline will be calculated as post-baseline value - baseline value. Increased hematocrit values indicate improvement. | Up to approximately 8.5 years | 
| Change From Baseline in Reticulocyte Count at Week 24 | Change (absolute change) from baseline was calculated as post-baseline value - baseline value. Decreased reticulocyte count values indicate improvement. | Baseline and Week 24 | 
| Change From Baseline in Reticulocyte Count Over the Duration of the Extension Period | Change (absolute change) from baseline will be calculated as post-baseline value - baseline value. Decreased reticulocyte count values indicate improvement. | Up to approximately 8.5 years | 
| Change From Baseline in Haptoglobin at Week 24 | Change (absolute change) from baseline was calculated as post-baseline value - baseline value. Increased haptoglobin values indicate improvement. | Baseline and Week 24 | 
| Change From Baseline in Haptoglobin Over the Duration of the Extension Period | Change (absolute change) from baseline will be calculated as post-baseline value - baseline value. Increased haptoglobin values indicate improvement. | Up to approximately 8.5 years | 
| Change From Baseline in Carbon Monoxide at Week 24 | Change (absolute change) from baseline was calculated as post-baseline value - baseline value. Decreased carbon monoxide values indicate improvement. | Baseline and Week 24 | 
| Change From Baseline in Carbon Monoxide Over the Duration of the Extension Period | Change (absolute change) from baseline will be calculated as post-baseline value - baseline value. Decreased carbon monoxide values indicate improvement. | Up to approximately 8.5 years | 
| Change From Baseline in Lactate Dehydrogenase (LDH) at Week 24 | Change (absolute change) from baseline was calculated as post-baseline value - baseline value. Decreased LDH values indicate improvement. | Baseline and Week 24 | 
| Change From Baseline in LDH Over the Duration of the Extension Period | Change (absolute change) from baseline will be calculated as post-baseline value - baseline value. Decreased LDH values indicate improvement. | Up to approximately 8.5 years | 
| Change From Baseline in Total Bilirubin at Week 24 | Change (absolute change) from baseline was calculated as post-baseline value - baseline value. Decreased total bilirubin values indicate improvement. | Baseline and Week 24 | 
| Change From Baseline in Total Bilirubin Over the Duration of the Extension Period | Change (absolute change) from baseline will be calculated as post-baseline value - baseline value. Decreased total bilirubin values indicate improvement. | Up to approximately 8.5 years | 
| Change From Baseline in Indirect Bilirubin at Week 24 | Change (absolute change) from baseline was calculated as post-baseline value - baseline value. Decreased indirect bilirubin values indicate improvement. | Baseline and Week 24 | 
| Change From Baseline in Indirect Bilirubin Over the Duration of the Extension Period | Change (absolute change) from baseline will be calculated as post-baseline value - baseline value. Decreased indirect bilirubin values indicate improvement. | Up to approximately 8.5 years | 
| Change From Baseline in Erythropoietin (EPO) at Week 24 | Change (absolute change) from baseline was calculated as post-baseline value - baseline value. Decreased EPO values indicate improvement. | Baseline and Week 24 | 
| Change From Baseline in EPO Over the Duration of the Extension Period | Change (absolute change) from baseline will be calculated as post-baseline value - baseline value. Decreased EPO values indicate improvement. | Up to approximately 8.5 years | 
| Change From Baseline in Hepcidin at Week 24 | Change (absolute change) from baseline was calculated as post-baseline value - baseline value. Decreased hepcidin values indicate improvement. | Baseline and Week 24 | 
| Change From Baseline in Hepcidin Over the Duration of the Extension Period | Change (absolute change) from baseline will be calculated as post-baseline value - baseline value. Decreased hepcidin values indicate improvement. | Up to approximately 8.5 years | 
| Change From Baseline in Ferritin at Week 24 | Change (absolute change) from baseline was calculated as post-baseline value - baseline value. Decreased ferritin values indicate improvement. | Baseline and Week 24 | 
| Change From Baseline in Ferritin Over the Duration of the Extension Period | Change (absolute change) from baseline will be calculated as post-baseline value - baseline value. Decreased ferritin values indicate improvement. | Up to approximately 8.5 years | 
| Change From Baseline in Transferrin Saturation at 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. | Baseline and Week 24 | 
| Change From Baseline in Transferrin Saturation Over the Duration of the Extension Period | Transferrin saturation is the ratio of serum iron to iron-binding capacity. Change (absolute change) from baseline will be calculated as post-baseline value - baseline value. Decreased transferrin saturation values indicate improvement. | Up to approximately 8.5 years | 
| 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 | Pre-dose pharmacokinetic concentrations, if any, were excluded from the pharmacokinetic analyses. | 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 | 
| Maximum Plasma Concentration (Cmax) for AG-348 and Its Metabolite AGI-8702 | Pre-dose pharmacokinetic concentrations, if any, were excluded from the pharmacokinetic analyses. | 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 | 
| Time to Reach Peak Plasma Concentration (Tmax) for AG-348 and Its Metabolite AGI-8702 | Pre-dose pharmacokinetic concentrations, if any, were excluded from the pharmacokinetic analyses. | 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 | 
| Apparent Clearance at Steady-State (Clss/F) for AG-348 and Its Metabolite AGI-8702 | Pre-dose pharmacokinetic concentrations, if any, were excluded from the pharmacokinetic analyses. | pre-dose, 0.5, 1, 2, 4, 8 hours post-dose Day 15 | 
| Maximum Change From Baseline Response Value Over 12 Hours Post-dose (BRmax) for Adenosine Triphosphate (ATP) | Pre-dose concentration observed on Day 1 was used as Baseline for calculation of change from baseline. | 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 | 
| Maximum Change From Baseline Response Value Over 12 Hours Post-dose (BRmax) for 2,3 - Diphosphoglycerate (2,3-DPG) | Pre-dose concentration observed on Day 1 was used as Baseline for calculation of change from baseline. | 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 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Pyruvate Kinase Deficiency, Hemolytic anemia, Pyruvate Kinase Isoform R (PKR), Drive PK