Extension Study of AG-348 in Adult Participants With Pyruvate Kinase Deficiency Previously Enrolled in AG-348-006 or AG348-C-007

Study Overview
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Brief Summary
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This is a multicenter, open-label, extension study to evaluate the long-term safety, tolerability, and efficacy of treatment with AG-348 in participants who were previously enrolled in Study AG348-C-006 or Study AG348-C-007.

Official Title
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An Open-Label, Multicenter, Extension Study of AG-348 in Adult Subjects With Pyruvate Kinase Deficiency Previously Enrolled in AG-348 Studies

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: Be willing and able to comply with study visits and procedures; Have signed written informed consent prior to participating in this extension study; Have completed either antecedent study AG348-C-006 or AG348-C-007 through the Part 2 Week 24 Visit; Cohorts 2 and 3: Have demonstrated clinical benefit from AG-348 treatment in the antecedent study, in the opinion of the Investigator; For women of reproductive potential, have a negative pregnancy test during screening; For women of reproductive potential as well as men with partners who are women of reproductive potential, be abstinent as part of their usual lifestyle, 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 study drug for women and 90 days following the last dose of study drug for men. Exclusion Criteria: Have a significant medical condition (including clinically significant laboratory abnormality) that developed during his/her antecedent AG- 348 study that confers an unacceptable risk to participating in this extension study, that could confound the interpretation of the study data, and/or that compromises the ability of the participant to complete study visits and procedures. Are currently pregnant or breastfeeding. Have a splenectomy scheduled during the study treatment period. Meet the withdrawal criteria of his/her antecedent AG-348 study during screening of this extension study. Are currently receiving medications that are strong inhibitors of cytochrome P450 (CYP)3A4 that have not been stopped for a duration of at least 5 days or a time frame equivalent to 5 half-lives (whichever is longer) before start of study drug; or strong inducers of CYP3A4 that have not been stopped for a duration of at least 28 days or a time frame equivalent to 5 half-lives (whichever is longer) before start of study drug on this extension study. Have received anabolic steroids, including testosterone preparations, within 28 days prior to start of study drug on this extension study. Have received hematopoietic stimulating agents (eg, erythropoietins, granulocyte colony stimulating factors, thrombopoietins) within 28 days prior to start of study drug on this extension study. Have exposure to any investigational drug other than AG-348, device, or procedure within 3 months prior to start of study drug on this extension study.

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: Non-Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Cohort 1<br>Participants who received placebo in Study AG348-C-006 will enroll in Cohort 1. Part 1 (Dose Optimization Period, 12 weeks): Participants will begin by receiving 5 milligrams (mg) orally, twice a day. Each participant's dose of AG-348 may be increased to 20 mg twice a day and then to 50 mg twice a day depending on their response to AG-348 and tolerability. Part 2 (Fixed Dose Period, 12 weeks): Last dose received in Part 1, twice a day. After completion of Part 2, participants who, in the opinion of the Investigator, have demonstrated clinical benefit from AG-348 treatment will continue AG-348 treatment in the Continued Treatment Period. | Drug: AG-348<br>* Participants will receive 5, 20, or 50 mg twice a day for up to 192 weeks (not including dose taper) unless the dose is modified for reasons related to safety.<br>|
| Experimental: Cohort 2<br>Participants who received AG-348 in Study AG348-C-006 will enroll in Cohort 2. Participants will continue the AG-348 dose regimen they were receiving at the last visit of Study AG348-C-006. | Drug: AG-348<br>* Participants will receive 5, 20, or 50 mg twice a day for up to 192 weeks (not including dose taper) unless the dose is modified for reasons related to safety.<br>|
| Experimental: Cohort 3<br>Participants who received AG-348 in Study AG348-C-007 will enroll in Cohort 3. Participants will continue the AG-348 dose regimen they were receiving at the last visit of Study AG348-C-007. | Drug: AG-348<br>* Participants will receive 5, 20, or 50 mg twice a day for up to 192 weeks (not including dose taper) unless the dose is modified for reasons related to safety.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants with Adverse Events (AEs) and Serious Adverse Events (SAEs) |  | From baseline to safety follow-up (up to 198 weeks) | 
| Number of Participants with AEs Leading to Dose Reduction, Treatment Interruption and Treatment Discontinuation |  | From baseline to safety follow-up (up to 198 weeks) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of Participants Achieving a Hemoglobin (Hb) Response in Participants Who Previously Received Placebo in Study AG348-C-006 |  | Weeks 16, 20, 24 | 
| Area Under the Concentration-Time Curve (AUC) of AG-348 in Participants Who Previously Received Placebo in Study AG348-C-006 |  | Week 12: pre-dose, post-dose at 30 minutes, 1 hour (h), 2 h, 4 h, 8 h | 
| Maximum Observed Concentration of AG-348 in Participants Who Previously Received Placebo in Study AG348-C-006 |  | Week 12: pre-dose, post-dose at 30 minutes, 1 h, 2 h, 4 h, 8 h | 
| Change from Baseline in Hb Concentration |  | From baseline up to Week 193 (Day 1) | 
| Change from Baseline in Bilirubin |  | From baseline up to Week 193 (Day 1) | 
| Change from Baseline in Lactate Dehydrogenase (LDH) |  | From baseline up to Week 193 (Day 1) | 
| Change from Baseline in Haptoglobin Levels |  | From baseline up to Week 193 (Day 1) | 
| Change from Baseline in Reticulocyte Percentages |  | From baseline up to Week 193 (Day 1) | 
| Change from Baseline in Number of Transfusion Events |  | From baseline up to Week 193 (Day 1) | 
| Change from Baseline in Number of Red Blood Cell (RBC) Units Transfused |  | From baseline up to Week 193 (Day 1) | 
| Change from Baseline in Health-Related Quality of Life (HRQoL) Patient-Reported Outcome (PRO) Scores: Pyruvate Kinase Deficiency Diary (PKDD) |  | From baseline up to Week 193 (Day 1) | 
| Change from Baseline in HRQoL PRO Scores: Pyruvate Kinase Deficiency Impact Assessment (PKDIA) |  | From baseline up to Week 193 (Day 1) |