A Study Evaluating the Efficacy and Safety of AG-348 in Regularly Transfused Adult Participants With Pyruvate Kinase Deficiency (PKD)

Study Overview
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Brief Summary
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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.

Official Title
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An Open-Label Study To Evaluate the Efficacy and Safety of AG-348 in Regularly Transfused Adult Subjects With Pyruvate Kinase (PK) Deficiency

Conditions
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Pyruvate Kinase Deficiency, Anemia, Hemolytic

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 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.

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
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: AG-348<br>Participants received AG-348 tablets, administered orally, at a starting dose of 5 milligrams (mg), twice daily (BID), followed by two sequential dose level increases to 20 mg and 50 mg BID, for a period of 16 weeks in Part 1. This was followed by optimized dose BID, as determined by the investigator in Part 1, for a period of 24 weeks in Part 2. | Drug: AG-348<br>* Part 1 (Dose Optimization Period): Participants began by receiving 5 mg orally, BID. Each participant's dose of AG-348 was sequentially increased to 20 mg BID followed by 50 mg BID depending on their response to AG-348 and their tolerance. Part 2 (Fixed Dose Period): Optimized dose determined in Part 1.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of Participants Achieving a Reduction in Transfusion Burden in Part 2 | Reduction in transfusion burden is defined as a ≥33% reduction in the number of RBC units transfused during the Fixed Dose Period standardized to 24 weeks compared with the historical transfusion burden standardized to 24 weeks (Standardized Control Period). The on-study (Fixed Dose Period) transfusion burden was calculated as the total number of transfused RBC units received in the Fixed Dose Period standardized to 24 weeks. | From Part 2, Day 1 to Part 2 Week 24 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Annualized Number of RBC Units Transfused During the Study | The annualized total number of RBC units transfused during the entire study (both Part 1 and Part 2) is reported. It was calculated as the total number of RBC units transfused up to the end of Fixed Dose Period divided by the total number of days from the first dose date until the end date of Fixed Dose Period × 52. | Part 1 Day 1 to Part 2 Week 24 | 
| Number of Transfusion Episodes in Part 2 | This is the number of transfusion episodes in Part 2. The number of transfusion episodes were standardized to 24 weeks. Transfusions received over up to 3 consecutive days were counted as 1 episode. | From Part 2 Day 1 to Part 2 Week 24 | 
| Percentage of Transfusion-Free Participants in Part 2 | Transfusion-free responders were the participants who were transfusion-free in Part 2. | From Part 2 Day 1 to Part 2 Week 24 | 
| Percentage of Participants Achieving Normal Hemoglobin (Hb) Concentrations in Part 2 | This is the percentage of participants who achieved hemoglobin (Hb) concentrations in the normal range at least once, 8 weeks or more after a transfusion in Part 2. | From Part 2 Day 1 to Part 2 Week 24 | 
| Percentage of Participants With Adverse Events | An AE is any untoward medical occurrence in a participant or clinical investigation participant administered a pharmaceutical product and which does not necessarily have to have a causal relationship with the study drug. An AE can, therefore, be any unfavorable and unintended sign (including an abnormal laboratory finding, for example), symptom, or disease temporally associated with the use of a medicinal product, whether or not considered related to the medicinal product. | Through 4 weeks after last dose (approximately Part 2, Week 31) |