Pyruvate Kinase Deficiency MedDRA version: 21.1 Level: PT Classification code 10037682 Term: Pyruvate kinase deficiency anaemia System Organ Class: 10010331 - Congenital, familial and genetic disorders
Conditions
Sponsors
Agios Pharmaceuticals, Inc.
Eligibility
Sex/Gender
All
Inclusion criteria
Inclusion criteria: 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 an Hb concentration less than or equal to 10.0 g/dL (6.21 mmol/L) regardless of gender (average of at least 2 Hb measurements [separated by a minimum of 7 days] during the Screening Period performed by the study central laboratory) 5. Be 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 6. Have 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 7. Have adequate organ function, as defined by: a. Serum aspartate aminotransferase (AST) =2.5 × 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 =1.0 × 109/L (based on an average of at least 2 measurements [separated by a minimum of 7 days] during the Screening Period, performed by the study central laboratory). e. Platelet count =100 × 109/L (based on an average of at least 2 measurements [separated by a minimum of 7 days] during the Screening Period, performed by the study central laboratory). f. Activated partial thromboplastin time and international normalized ratio =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 (both men and women) following the last dose of study treatment. A highly effective form of contraception is defined as combined (estrogen and progestin containing) hormonal contraceptives (oral, intravaginal, or transd
Exclusion criteria
Exclusion criteria: 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 >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, hepatic, or pancreatic 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. i. Positive test for HBsAg or HCVAb 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 HIV-1 or -2 Ab k. Active infection requiring the use of parenteral antimicrobial agents or Grade =3 in severity within 2 months prior to the first dose of study treatment 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, could compromise the ability of the subject to cooperate with study visits and procedures 3. Splenectomy scheduled during the study treatment period or have undergone splenectomy within 12 months prior to signing informed consent 4. Currently enrolled in another therapeutic clinical trial involving ongoing therapy with any investigational or marketed product or placebo. 5. Exposure to any investigational drug, device, or procedure within 3 months prior to t
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| Main Objective: To evaluate the efficacy of treatment with AG-348 compared with placebo in increasing hemoglobin (Hb) concentrations;Secondary Objective: Secondary: • To evaluate the safety of AG-348 • To determine the effect of the study treatment regimens on markers of hemolysis, hematopoietic activity, and other indicators of clinical activity • To determine the effect of the study treatment regimens on health-related quality of life (HRQoL), as determined using patient-reported outcomes (PROs) • To evaluate the pharmacokinetics of AG-348 after oral administration • To evaluate the relationship between AG-348 pharmacokinetics and safety parameters Exploratory: • To evaluate the relationship of AG-348 pharmacokinetics to indicators of clinical activity • To evaluate the pharmacodynamic markers of pyruvate kinase deficiency (PK deficiency) and how they are affected by study treatment • To determine the effect of the study treatment regimens on: o Number of transfusion events and number of red blood cell (RBC) units transfused o Markers of iron metabolism and indicators of iron overload ;Primary end point(s): The primary endpoint is the hemoglobin response, defined as a =1.5 g/dL (0.93 mmol/L) increase in Hb concentration from baseline that is sustained at 2 or more scheduled assessments at Weeks 16, 20, and 24 during the Fixed Dose Period. The individual subject’s baseline Hb concentration is defined as the average of all available Hb concentrations from the central laboratory for that subject during the Screening Period up to the first dose of study treatment.;Timepoint(s) of evaluation of this end point: Weeks 16, 20 & 24 during the fixed dose period | — |
Secondary
| Measure | Time frame |
|---|---|
| Secondary end point(s): Key secondary endpoint: • Average change from baseline in Hb concentration at Weeks 16, 20, and 24 Other secondary endpoint: • Maximal Hb concentration increase from baseline • Time to first achieve an increase in Hb concentration of 1.5 g/dL (0.93 mmol/L) or more from baseline • Average change from baseline at Weeks 16, 20, and 24 in markers of hemolysis: bilirubin, LDH, and haptoglobin levels • Average change from baseline at Weeks 16, 20, and 24 in markers of hematopoietic activity: reticulocyte percentages • Change from baseline in HRQoL PRO scores: Pyruvate Kinase Deficiency Diary (PKDD) and Pyruvate Kinase Deficiency Impact Assessment (PKDIA) • Safety endpoints, including: the type, incidence, severity, and relationship to study treatment of AEs and SAEs; number of discontinuations due to AEs; results of clinical laboratory tests over time (eg, serum chemistry, LFT, hematology, lipids, sex steroids, urinalysis, coagulation); physical examination (PE) findings; dual-energy x-ray absorption (DXA) scans; vital signs; 12-lead electrocardiogram (ECG) data • Pharmacokinetic endpoints, including plasma concentrations over time and pharmacokinetic parameters of AG-348 (eg, AUC, Cmax, others as applicable) • Exposure-response relationship between safety parameters and AG-348 concentration and relevant AG-348 pharmacokinetic parameters Exploratory endpoint: • Exposure-response (or pharmacokinetic-pharmacodynamic) relationship between relevant pharmacokinetic parameters and endpoints that are indicators of clinical activity • Change from baseline in additional markers of hematopoietic activity • Change from baseline in markers of iron metabolism and indicators of iron overload • Change from baseline in PKR protein level • Relationship between baseline PKR protein level and Hb response status • Change from baseline in HRQoL PRO scores: European quality of life five-dimensional descriptive system (EQ-5D-5L) • Change from baseline in PKR flux assay | — |
Countries
Canada, Czech Republic, Denmark, France, Germany, Italy, Japan, Korea, Republic of, Netherlands, Poland, Portugal, Spain, Switzerland, Thailand, United Kingdom, United States
Contacts
Public ContactDirector, Scientific Communications
Agios Pharmaceuticals, Inc.
Outcome results
None listed