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 and 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 of oral folic acid daily for at least 21 days prior to the first dose of IMP, to be continued daily during study participation. 7. Have adequate organ function, as defined by: a. Serum AST =2.5 × ULN (unless the increased AST is assessed by the Investigator as due to hemolysis and/or hepatic iron deposition) and 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 × 10^9/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 (FSH) 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 IMP for women and 90 days following the last dose of IMP 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
Exclusion criteria
Exclusion criteria: 1.Homozygous for R479H mutation or 2 non-missense mutations without presence of another missense mutation in the PKLR gene, as determined per genotyping performed by the study central genotyping lab 2.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 not limited to the following: a.Poorly controlled hypertension (defined as systolic BP>150mmHg or diastolic BP>90mmHg) refractory to medical management b.History of recent (within 6 months prior to 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 clinically significant by Investigator d.Heart-rate corrected QTcF>450msec with 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 disorder treated and clinical symptoms 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 HBsAg or HCVAb with signs of active hepatitis B or C virus infection. If subject positive for HCVAb, RT-PCR 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 (per NCI CTCAE) within 2 months prior to the first dose of IMP l.Diabetes mellitus judged to be under poor control by Investigator or requiring >3 antidiabetic agents, including insulin (all insulins considered 1 agent); use of insulin per se is not exclusionary m.History of any primary malignancy with 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 last 3 years n.Unstable extramedullary hematopoiesis that could pose a risk of imminent neurologic compromise o.Current/recent history of psychiatric disorder that, in opinion of Investigator/Medical Monitor (or designee) could compromise ability of subject to cooperate with study visits and procedures 3.History of transfusions occurring on average more frequently than once every 3 weeks during the 52 weeks prior to signing ICF 4.Splenectomy scheduled during the study drug period or have undergone splenectomy within 12 months prior to signing ICF 5.Currently enrolled in another therapeutic clinical trial involving ongoing therapy with any investigational or marketed product or placebo. Prior/subsequent participati
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| Main Objective: The primary objective of the study is to evaluate the efficacy of treatment with AG-348, as assessed by the reduction in transfusion burden.;Secondary Objective: The secondary objective of this study is to evaluate the safety of treatment with AG-348. Exploratory objectives are: • To determine the effect of AG-348 on makers of hemolysis, erythropoietic activity, and other indicators of clinical activity • To determine the effect of AG-348 on markers of iron metabolism and indicators of iron overload • To determine the effect of AG-348 on health-related quality of life (HRQoL), as determined using patient-reported outcomes • To evaluate the pharmacokinetics of AG-348 after oral administration • To evaluate the relationship of AG-348 pharmacokinetics to indicators of clinical activity • To evaluate the change in the levels of red blood cell (RBC) -specific form of pyruvate kinase (PKR) protein in whole blood;Primary end point(s): The primary endpoint of this study is the proportion of subjects who achieve a reduction in transfusion burden, defined as a =33% reduction in the number of RBC units transfused during the 24 weeks of Part 2 compared with the historical transfusion burden standardized to 24 weeks (Standardized Control Period).;Timepoint(s) of evaluation of this end point: All through the study: for each transfusion administered at any time during the study, the date of transfusion, number of RBC units transfused, HCT, and volume of RBC units will be recorded. | — |
Secondary
| Measure | Time frame |
|---|---|
| Secondary end point(s): Secondary Endpoints The secondary endpoints of the study are the following: • Annualized total number of RBC units transfused during the study (both Part 1 and Part 2) compared with the historical transfusion burden • Number of transfusion episodes during Part 2 compared to the Standardized Control Period • Proportion of subjects who become transfusion-free, defined as 0 transfusions administered during Part 2 • Proportion of subjects who achieve Hb concentrations in the normal range at least once, 8 weeks or more after a transfusion in Part 2 • Safety endpoints, including the type, incidence, severity, and relationship to treatment of adverse events (AEs) and serious adverse events (SAEs) and AEs leading to treatment dose reduction, treatment interruption, and treatment discontinuation • Laboratory tests over time (eg. serum chemistry/liver function tests/[LFTs], coagulation, lipids, sex steroids, urinalysis), physical examination findings, dual energy X-ray absorptiometry (DXA) scans (hip and lumbar spine), vital signs, and 12-lead electrocardiograms (ECG) data Exploratory Endpoints The exploratory endpoints of the study are the following: • Change from baseline in the following markers of hemolysis: bilirubin, lactate dehydrogenase (LDH), and haptoglobin levels • Change from baseline in markers of erythropoietic activity • Change from baseline in markers of iron and indicators of iron overload • Changes from baseline over time in HRQoL scores (ie. Pyruvate Kinase Deficiency Impact Assessment [PKDIA], Pyruvate Kinase Deficiency Diary [PKDD], EuroQol-5D-5L [EQ-5D-5L] • Characterization of pharmacokinetic profile (drug concentrations over time) and determination of pharmacokinetic parameters of AG-348 (eg, area under the plasma concentration × time curve [AUC], maximum [peak] concentration [Cmax], and others as applicable) in Part 2 • Exposure-response (or pharmacokinetic-pharmacodynamics) relationship between relevant pharmacokinetic param | — |
Countries
Canada, Czech Republic, Denmark, France, Ireland, Italy, Netherlands, Spain, Thailand, Turkey, United Kingdom, United States
Contacts
Public ContactDirector, Scientific Communications
Agios Pharmaceuticals, Inc.
Outcome results
None listed