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

1. Have provided signed written informed consent prior to performing any study
procedure, including screening procedures.
2. Be aged 18 years or older.
3. Have documented clinical laboratory confirmation of 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, as determined per the genotyping performed
by the study central genotyping laboratory.
4. Have a history of a minimum of 6 transfusion episodes in the 52-week period
prior to date of informed consent as documented in the transfusion history of
the subject, which reflects the subject*s typical transfusion burden.
5. Have complete records of transfusion history, defined as having the
following available for the 52 weeks prior to the date of informed consent: (1)
all the transfusion dates, (2) the number of blood units transfused for all the
transfusions, and (3) Hb concentrations within 1 week prior to transfusion for
at least 80% of the transfusions.
6. Have received at least 0.8 mg oral folic acid daily for at least 21 days
prior to the first dose of study drug, to be continued daily during study
participation.
7. Have adequate organ function, as defined by:
a. Serum aspartate aminotransferase (AST) <=2.5 × upper limit of normal (ULN)
(unless the increased AST is assessed by the Investigator as due to hemolysis
and/or hepatic iron deposition) and alanine aminotransferase (ALT) <=2.5 × ULN
(unless the increased ALT is assessed by the Investigator as due to hepatic
iron deposition).
b. Normal or elevated levels of serum bilirubin. In subjects with serum
bilirubin >ULN, the elevation must not be associated with choledocholithiasis,
cholecystitis, biliary obstruction, or hepatocellular disease. Elevated
bilirubin attributed to hemolysis with or without Gilbert*s syndrome is not
exclusionary.
c. Estimated glomerular filtration rate (GFR) >=60 mL/min/1.73 m2, measured GFR
>=60 mL/min, or calculated creatinine clearance (CrCL; Cockcroft-Gault) >=60
mL/min.
d. Absolute neutrophil count (ANC) >=1.0 × 109/L.
e. Platelet count >=100 × 109/L, in the absence of a spleen, or platelet count
>=50 × 109/L, in the presence of a spleen and in the absence of any other cause
of thrombocytopenia.
f. Activated partial thromboplastin time (aPTT) and international normalized
ratio (INR) <=1.25 × ULN, unless the subject is receiving therapeutic
anticoagulants.
8. For women of reproductive potential, have a negative serum pregnancy test
during the Screening Period. Women of reproductive potential are defined as
sexually mature women who have not undergone a hysterectomy, bilateral
oophorectomy, or tubal occlusion or who have not been naturally postmenopausal
(ie, who have not menstruated at all for at least the preceding 12 months prior
to signing informed consent and have an elevated follicle stimulating hormone
level indicative of menopause during the Screening Period).
9. 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. A highly effective form of contraception
is defined as combined (estrogen and progestin containing) hormonal
contraceptives (oral, intravaginal, or transdermal) known to be associated with
inhibition of ovulation; progestin-only hormonal contraceptives (oral,
injectable, or implantable) known to be associated with inhibition of
ovulation; intrauterine device; intrauterine hormone releasing system;
bilateral tube occlusion; or vasectomized partner. The second form of
contraception can include an acceptable barrier method, which includes male or
female condoms with or without spermicide, and cervical cap, diaphragm, or
sponge with spermicide. Women of reproductive potential using hormonal
contraception as a highly effective form of contraception must also utilize an
acceptable barrier method while enrolled in the study and for at least 28 days
after their last dose of study drug.
10. Be willing to comply with all study procedures, in particular the
Individual TT (calculated based on 52 weeks of transfusion history), for the
duration of the study.

1. Are homozygous for the R479H mutation or have 2 non-missense mutations
without the presence of another missense mutation in the PKLR gene, as
determined per the genotyping performed by the study central genotyping
laboratory.
2. Have a significant medical condition that confers an unacceptable risk to
participating in the study and/or that could confound the interpretation of the
study data. Such significant medical conditions include, but are not limited
to, the following:
a. Poorly controlled hypertension (defined as systolic blood pressure [BP] >150
mmHg or diastolic BP >90 mmHg) refractory to medical management.
b. History of recent (within 6 months prior to signing informed consent)
congestive heart failure; myocardial infarction or unstable angina pectoris;
hemorrhagic, embolic, or thrombotic stroke; deep venous thrombosis; or
pulmonary or arterial embolism.
c. Cardiac dysrhythmias judged as clinically significant by the Investigator.
d. Heart-rate corrected QT interval-Fridericia*s method (QTcF) >450 msec with
the exception of subjects with right or left bundle branch block.
e. Clinically symptomatic cholelithiasis or cholecystitis. Prior
cholecystectomy is not exclusionary. Subjects with symptomatic cholelithiasis
or cholecystitis may be rescreened once the disorder has been treated and
clinical symptoms have resolved.
f. History of drug-induced cholestatic hepatitis.
g. Iron overload sufficiently severe to result in a clinical diagnosis by the
Investigator of cardiac (eg, clinically significant impaired left ventricular
ejection fraction), hepatic (eg, fibrosis, cirrhosis), or pancreatic (eg,
diabetes) dysfunction.
h. Diagnosis of any other congenital or acquired blood disorder or any other
hemolytic process, except mild allo-immunization, as a consequence of
transfusion therapy. Genetic findings that in isolation are predicted to be
insufficient to explain the observed clinical phenotype may be allowed (eg,
heterozygous status for certain recessive RBC disorders).
i. Positive test for hepatitis B surface antigen (HBsAg) or hepatitis C virus
(HCV) antibody (Ab) with signs of active hepatitis B or C virus infection. If
the subject is positive for HCVAb, a reverse transcriptase-polymerase chain
reaction test will be conducted. Subjects with hepatitis C may be rescreened
after receiving appropriate hepatitis C treatment.
j. Positive test for human immunodeficiency virus-1 or -2 Ab.
k. Active infection requiring the use of parenteral antimicrobial agents or
Grade >=3 in severity (per National Cancer Institute Common Terminology Criteria
for Adverse Events [NCI CTCAE]) within 2 months prior to the first dose of
study drug.
l. Diabetes mellitus judged to be under poor control by the Investigator or
requiring >3 antidiabetic agents, including insulin (all insulins are
considered 1 agent); use of insulin per se is not exclusionary.
m. History of any primary malignancy, with the exception of curatively treated
nonmelanomatous skin cancer; curatively treated cervical or breast carcinoma in
situ; or other primary tumor treated with curative intent, no known active
disease present, and no treatment administered during the last 3 years.
n. Unstable extramedullary hematopoiesis that could pose a risk of imminent
neurologic compromise.
o. Current or recent history of psychiatric disorder that, in the opinion of
the Investigator or Medical Monitor (or designee), could compromise the ability
of the subject to cooperate with study visits and procedures.
3. Have a history of transfusions occurring on average more frequently than
once every 3 weeks during the 52 weeks prior to signing informed consent.
4. Have a splenectomy scheduled during the study drug period or have undergone
splenectomy within 12 months prior to signing informed consent.
5. Are 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. Therefore, subjects enrolling in this current study will
be expected to temporarily suspend participation in the NHS or Registry.
6. Have exposure to any investigational drug, device, or procedure within 3
months prior to the first dose of study drug.
7. Have a prior bone marrow or stem cell transplant.
8. Are currently pregnant or breastfeeding.
9. Have a history of major surgery within 6 months of signing informed consent.
Note that procedures such as laparoscopic gallbladder surgery are not
considered major in this context.
10. Are 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 drug.
11. Are 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.
12. Have a 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.
13. Have a history of allergy to AG-348 or its excipients (microcrystalline
cellulose, croscarmellose sodium, sodium stearyl fumarate, and mannitol).
14. Are currently receiving anabolic steroids, including testosterone
preparations, within 28 days prior to the first dose of study drug.