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

Agios Pharmaceuticals

Status and phase: Completed; Phase 3

Conditions: Anemia, Hemolytic; Pyruvate Kinase Deficiency

Treatments: Drug: AG-348; Drug: Placebo

Study type: Interventional

Funder types: Industry

Identifiers

NCT03548220

AG348-C-006

Details and patient eligibility

About

Study AG348-C-006 evaluated the efficacy and safety of orally administered AG-348 as compared with placebo in participants with pyruvate kinase (PK) deficiency, who were not regularly receiving blood transfusions. Participants were randomized 1:1 to receive either AG-348 or a matching placebo.

Enrollment: 80 patients

Sex: All

Ages: 18+ years old

Volunteers: No Healthy Volunteers

Inclusion criteria

• Informed consent;
• Male or female, aged 18 years or older;
• Documented clinical laboratory confirmation of pyruvate kinase (PK) deficiency, defined as documented presence of at least 2 mutant alleles in the PKLR gene, of which at least 1 is a missense mutation;
• Hemoglobin (Hb) concentration less than or equal to 10.0 grams per deciliter (g/dL) regardless of gender (average of at least 2 Hb measurements [separated by a minimum of 7 days] during the Screening Period)
• 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 treatment;
• 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.

Trial design

Primary purpose: Treatment

Allocation: Randomized

Interventional model: Parallel Assignment

Masking: Triple Blind

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80 participants in 4 patient groups, including a placebo group

Placebo

Placebo Comparator group

Description:

Participants received a matching placebo to AG-348 tablets, for a period of 12 weeks as an optimized dose. This was followed by matching placebo further, for a period of 12 weeks as a fixed-dose.

Treatment:

Drug: Placebo

AG-348, 5 mg

Experimental group

Description:

Participants received AG-348 tablets, 5 milligrams (mg) twice daily (BID), administered orally, for 4 weeks as a starting dose, followed by two potential sequential dose level increases to 20 mg and 50 mg BID at Weeks 4 and 8 respectively as determined by the investigator based on safety and efficacy. The optimized dose for each participant was determined as 5 mg BID at Week 12, and participants then received that optimized dose for a period of 12 weeks as a fixed dose.

Treatment:

Drug: AG-348

AG-348, 20 mg

Experimental group

Description:

Participants received AG-348 tablets, 5 mg BID, administered orally, for 4 weeks as a starting dose, followed by two potential sequential dose level increases to 20 mg and 50 mg BID at Weeks 4 and 8 respectively as determined by the investigator based on safety and efficacy. The optimized dose for each participant was determined as 20 mg BID at Week 12, and participants then received that optimized dose for a period of 12 weeks as a fixed dose.

Treatment:

Drug: AG-348

AG-348, 50 mg

Experimental group

Description:

Participants received AG-348 tablets, 5 mg BID, administered orally, for 4 weeks as a starting dose, followed by two potential sequential dose level increases to 20 mg and 50 mg BID at Weeks 4 and 8 respectively as determined by the investigator based on safety and efficacy. The optimized dose for each participant was determined as 50 mg BID at Week 12, and participants then received that optimized dose for a period of 12 weeks as a fixed dose.

Treatment:

Drug: AG-348