Purpose

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 will be optimized individually, up to a maximum dose of 50 milligrams (mg), twice daily. During the Part 2 Fixed-Dose Period, participants will receive AG-348 at their optimized dose from Part 1.

Conditions

Eligibility

Eligible Ages
Over 18 Years
Eligible Genders
All
Accepts Healthy Volunteers
No

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 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 (both men and women) 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 participation in the PK Deficiency Natural History Study (NHS) (NCT02053480) or PK Deficiency Registry is permitted; 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.

Study Design

Phase
Phase 3
Study Type
Interventional
Allocation
Randomized
Intervention Model
Parallel Assignment
Primary Purpose
Treatment
Masking
Triple (Participant, Care Provider, Investigator)

Arm Groups

ArmDescriptionAssigned Intervention
Experimental
AG-348
Part 1 (Dose Optimization Period): Participants will receive AG-348 for 12 weeks. Investigators will assess the need for dose increases every 4 weeks. Part 2 (Fixed Dose Period): Participants will receive their optimized dose of AG-348 as determined by the individual's response in Part 1.
  • Drug: AG-348
    Part 1 (Dose Optimization Period): 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 or 50 mg twice a day depending on their response to AG-348 and their tolerance. Part 2 (Fixed Dose Period): Last dose received in Part 1, twice daily.
Placebo Comparator
Placebo
Part 1 (Dose Optimization Period): Participants will receive placebo matching AG-348 for 12 weeks. Investigators will assess the need for dose increases every 4 weeks. Part 2 (Fixed Dose Period): Participants will receive their optimized dose of placebo matching AG-348 as determined by the individual's response in Part 1.
  • Drug: Placebo
    Part 1 (Dose Optimization Period): Participants will begin by receiving placebo matching AG-348 orally, twice a day. Each participant's dose of placebo matching AG-348 may be increased to 20 mg twice a day or 50 mg twice a day depending on their response to the placebo matching AG-348 and their tolerance. Part 2 (Fixed Dose Period): Last dose received in Part 1, twice daily.

Recruiting Locations

Massachusetts General Hospital
Boston, Massachusetts 46260

More Details

NCT ID
NCT03548220
Status
Recruiting
Sponsor
Agios Pharmaceuticals, Inc.

Study Contact

Medical Affairs
833-228-8474
medinfo@agios.com

Notice

Study information shown on this site is derived from ClinicalTrials.gov (a public registry operated by the National Institutes of Health). The listing of studies provided is not certain to be all studies for which you might be eligible. Furthermore, study eligibility requirements can be difficult to understand and may change over time, so it is wise to speak with your medical care provider and individual research study teams when making decisions related to participation.