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A Study to Evaluate Efficacy and Safety of AG-348 in Not Regularly Transfused Adult Participants With Pyruvate Kinase Deficiency (PKD) ID: NCT03548220


Study AG348-C-006 will evaluate the efficacy and safety of orally administered AG-348 as compared with placebo in participants with pyruvate kinase deficiency (PKD), who are not regularly receiving blood transfusions. Participants will be randomized 1:1 to receive either AG-348 or matching placebo. The study is comprised of two parts. During the Part 1 Dose Optimization Period of the study, participants will start on a dose of 5 mg AG-348 administered twice daily. Over the course of Part 1, each participant's dose of AG-348 may be sequentially increased to 20 mg twice a day, followed by 50 mg twice a day depending on their tolerance. During the Part 2 Fixed-Dose Period, participants will receive AG-348 at their optimized dose from Part 1.


Pyruvate Kinase Deficiency

Anemia Hemolytic

Recruitment Status



Eligibility Criteria

Inclusion Criteria:

- Informed consent;

- Male or female, aged 18 years or older;

- Documented clinical laboratory confirmation of pyruvate kinase deficiency (PKD),
defined as documented presence of at least 2 mutant alleles in the PKLR gene, of which
at least 1 is a missense mutation;

- Hb concentration less than or equal to 10.0 g/dL regardless of gender (average of at
least 2 Hb measurements [separated by a minimum of 7 days] during the Screening

- Considered not regularly transfused, defined as having had no more than 4 transfusion
episodes in the 12-month period up to the first day of study treatment and no
transfusions in the 3 months prior to the first day of study treatment;

- Received at least 0.8 mg oral folic acid daily for at least 21 days prior to the first
dose of study treatment, to be continued daily during study participation.

- Adequate organ function;

- Women of reproductive potential, have a negative serum pregnancy test;

- 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 treatment for women and 90 days for men following the last dose of study

- Willing to comply with all study procedures 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 participating in
the study, and/or that could confound the interpretation of the study data;

- 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 involving ongoing therapy
with any investigational or marketed product or placebo. Prior and subsequent
participation in the PK Deficiency Natural History Study (NHS) (NCT02053480) or PK
Deficiency Registry is permitted however, concurrent participation is not;
participants enrolling in this current study will be expected to temporarily suspend
participation in the NHS or Registry;

- Exposure to any investigational drug, device, or procedure within 3 months prior to
the first dose of study treatment;

- Prior treatment with a pyruvate kinase activator;

- 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 cytochrome P450
(CYP)3A4, 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 a timeframe equivalent to 5 half-lives (whichever is
longer) prior to the first dose of study treatment;

- Currently receiving hematopoietic stimulating agents that have not been stopped for a
duration of at least 28 days prior to the first dose of study treatment;

- 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;

- History of allergy to AG-348 or its excipients;

- Currently receiving anabolic steroids, including testosterone preparations, within 28
days prior to treatment.


Intervention Type


Intervention Name


Intervention Type


Intervention Name



Phase 3



Minimum Age

18 Years

Maximum Age


Download Date

November 11, 2020

Principal Investigator

Rachael Grace

Primary Contact Information

Joanne Crandall

For more information and to contact the study team:

For more information on this trial, visit

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