Healthcare Professionals

The ACTIVATE and ACTIVATE-T Phase 3 clinical trials are actively recruiting adult patients with pyruvate kinase (PK) deficiency. These studies will evaluate the safety and efficacy of AG-348, an investigational, orally available, small molecule activator of pyruvate kinase-R (PKR).

Diagnosing PK Deficiency

PK deficiency is an underdiagnosed cause of chronic, hereditary hemolytic anemia.1,2 If you suspect a patient may have PK deficiency, the diagnosis can be confirmed by analysis of PK enzymatic activity (enzyme assay) and genetic testing documenting the presence of mutations in the PKLR gene.

Note that study inclusion criteria state the eligible patient must have 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.

 

  1. Zanella A, et al. Br J Haematol. 2005;130(1):11-25.
  2. Pyruvate Kinase Deficiency. https://ghr.nlm.nih.gov/condition/pyruvate-kinase-deficiency. Accessed March 15, 2018.

 

AG-348 and PKR Enzyme Activation

AG-348 is an investigational, potent, broad-spectrum activator of PKR, one of four pyruvate kinase isoenzymes expressed in human tissues from two separate genes. Both PKR and the liver-specific form of pyruvate kinase (PKL) are alternative splice isoforms of the PKLR gene, while pyruvate kinase muscle isozymes PKM1 and PKM2 are both expressed from the PKM gene. AG-348 is an allosteric activator of the PKR, PKL, and PKM2 isoenzymes, with similar activity for each. AG-348 acts by directly binding to the PKR tetramer and allosterically enhancing its affinity for phosphoenolpyruvate (PEP).

In patients with PK deficiency, activity of the glycolytic pathway is disrupted. This disruption results in significantly reduced RBC lifespan and manifests clinically as nonspherocytic hemolytic anemia. In patients with PK deficiency, RBCs and their progenitors are characterized by changes in metabolism associated with defective glycolysis, including a buildup of PEP and the intermediate 2,3-DPG, and lowered levels of ATP. It is hypothesized that AG-348 may restore the ability of RBCs to convert PEP + ADP to pyruvate + ATP and thereby normalizes RBC metabolism in cells of patients with PK deficiency who have certain genotypes.3

AG-348 has been evaluated in two completed clinical pharmacology studies in healthy subjects (AG348-C-001 [NCT021108106] and AG348-C-002 [NCT02149966]). A Phase 2, multicenter, randomized, open-label, efficacy, and safety study of AG-348 in transfusion-independent* adult patients with PK deficiency is active but not recruiting (AG348-C-003, referred to as DRIVE-PK [NCT02476916]). Data from this Phase 2 study were presented at the 2017 American Society of Hematology (ASH) Meeting.4

AG-348 is now being evaluated in a Phase 3 trial involving patients with PK deficiency who are not regularly transfused (ACTIVATE [NCT03548220]) and in another Phase 3 trial involving patients who receive regular blood transfusions (ACTIVATE-T [NCT03559699]).

The safety and efficacy of AG-348 have not been established. There is no guarantee that AG-348 will receive health authority approval or become commercially available in any country for the use being investigated.

Mutant PKR Protein

* In the Phase 2 study, transfusion-independence was defined as having had ≤ 3 units of RBCs transfused in the 12-month period up to the first day of study drug dosing and no transfusions within 4 months of the first day of study dosing.

 

  1. Kung C, et al. Blood 2017;130(11):1347-1356.
  2. Grace RF, et al. Blood 2017; 130:2194. Available at http://www.bloodjournal.org/content/130/Suppl_1/2194. Accessed May 8, 2018.

Learn More About the Phase 3 Trials

Select a Study

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Agios Activate-T Clinical Trail Logo

Agios Activate Clinical Trial Logo

ACTIVATE Clinical Trial

Study Design and Objectives

The primary objective of the ACTIVATE Phase 3 study is to evaluate the efficacy of treatment with AG- 348, as assessed by a sustained increase in hemoglobin (Hb) concentrations.

The secondary objectives of this study are to:

  • Evaluate the safety of treatment with AG-348
  • Determine the effect of study treatment regimens on markers of hemolysis, hematopoietic activity, and other indicators of clinical activity
  • Determine the effect of study treatment regimens on health-related quality of life (HRQoL), as determined using patient-reported outcomes (PROs)
  • Evaluate the pharmacokinetics of AG-348 following oral administration
  • Evaluate the relationship between AG-348 pharmacokinetics and safety parameters

Additional objectives to be explored:

  • Evaluate the relationship of AG-348 pharmacokinetics to indicators of clinical activity
  • Evaluate the pharmacodynamic markers of pyruvate kinase deficiency (PK deficiency) and how they are affected by study treatment
  • Determine the effect of the study treatment regimens on:
    • Number of transfusion events and number of red blood cell (RBC) units transfused
    • Use and amount used of iron chelation therapy
    • Liver iron concentration (LIC)

Trial Design for Not Regularly Transfused Patients Chart

Study Criteria

inclusion Criteria

Key patient inclusion criteria include the following:

  • Age 18 years or older.
  • Have documented presence of at least 2 mutant alleles in the PKLR gene, of which at least 1 is a missense mutation (genomic testing will be provided by the study).
  •  Have an 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 performed by the study central laboratory).
  • 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.
  • Have received at least 0.8 mg of oral folic acid daily for at least 21 days priorto the first dose of study drug, to be continued daily during study participation.
  • Have adequate organ function.

Key exclusion Criteria
  1. Be homozygous for the R479H mutation or have 2 non-missense mutations 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 participate in the study, and/or that could confound the interpretation of the study data.
    1. Poorly controlled hypertension (defined as systolic blood pressure [BP] >150 mmHg or diastolic BP >90 mmHg) refractory to medical management.
    2. 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.
    3. Cardiac dysrhythmias judged as clinically significant by the Investigator.
    4. Heart-rate corrected QT interval-Fridericia’s method (QTcF) >450 msec with the exception of subjects with right or left bundle branch block.
    5. 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.
    6. History of drug-induced cholestatic hepatitis.
    7. 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.
    8. Have a diagnosis of any other congenital or acquired blood disorder, or any other hemolytic process, except mild allo-immunization as a consequence of transfusion therapy.
    9. Positive test for hepatitis B surface antigen 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.
    10. Positive test for human immunodeficiency virus 1 or 2 Ab.
    11. Active infection requiring the use of parenteral antimicrobial agents or Grade ≥3 in severity (per National Cancer Institute Common Terminology Criteria for Adverse Events) within 2 months prior to the first dose of study treatment.
    12. 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.
    13. 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.
    14. Unstable extramedullary hematopoiesis that could pose a risk of imminent neurologic compromise.
    15. 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.

Visit ClinicalTrials.gov to locate a clinical trial site near you.

Locate a clinical trial site

ACTIVATE-T Clinical Trial

Study Design and Objectives

The primary objective of this Phase 3 study is to evaluate the efficacy of treatment with AG-348, as assessed by the reduction in transfusion burden.
The secondary objective of this study is to evaluate the safety of treatment
with AG-348.

Additional objectives to be explored:

  • Determine the effect of AG-348 on liver iron status, as measured by:
    • Liver iron concentration
    • Use of iron chelation therapy
  • Evaluate health-related quality of life (HRQoL), as determined using patient-reported outcomes (PROs)
  • Evaluate the pharmacokinetics of AG-348 following oral administration
  • Evaluate the change in the levels of red blood cell-specific form of pyruvate kinase (PKR) protein in whole blood
Agios Activate-T Clinic Trial Logo

Trial Design for Regularly Transfused Patients

Study Criteria

inclusion Criteria

Key patient inclusion criteria include the following:

  • Age 18 years or older.
  • Have documented presence of at least 2 mutant alleles in the PKLR gene, of which at least 1 is a missense mutation (genomic testing will be provided by the study).
  • Have a documented history of 6 or more transfusions in the 52-week period prior to date of informed consent that includes:
    • All transfusion dates.
    • Number of blood units transfused for all transfusions.
    • Hemoglobin (Hb) levels within 1 week prior to transfusion (for at least 80% of transfusions).
  • Have received at least 0.8 mg of oral folic acid daily for at least 21 days prior to the first dose of study drug, to be continued daily during study participation.
  • Have adequate organ function.
Key exclusion Criteria
  1. Be homozygous for the R479H mutation or have 2 non-missense mutations 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 participate in the study, and/or that could confound the interpretation of the study data.
    1. Poorly controlled hypertension (defined as systolic blood pressure [BP] >150 mmHg or diastolic BP >90 mmHg) refractory to medical management.
    2. 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.
    3. Cardiac dysrhythmias judged as clinically significant by the Investigator.
    4. Heart-rate corrected QT interval-Fridericia’s method (QTcF) >450 msec with the exception of subjects with right or left bundle branch block.
    5. 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.
    6. History of drug-induced cholestatic hepatitis.
    7. 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.
    8. Have a diagnosis of any other congenital or acquired blood disorder, or any other hemolytic process, except mild allo-immunization, as a consequence of transfusion therapy.
    9. Positive test for hepatitis B surface antigen 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 re-screened after receiving appropriate hepatitis C treatment.
    10. Positive test for human immunodeficiency virus 1 or 2 Ab.
    11. Active infection requiring the use of parenteral antimicrobial agents or Grade ≥3 in severity (per National Cancer Institute Common Terminology Criteria for Adverse Events) within 2 months prior to the first dose of study treatment.
    12. 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.
    13. 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.
    14. Unstable extramedullary hematopoiesis that could pose a risk of imminent neurologic compromise.
    15. Current or recent history of psychiatric disorder that, in the opinion of the Investigator or the Medical Monitor, 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 the ICF.
Learn more about ACTIVATE-T at clinicaltrials.gov

Visit ClinicalTrials.gov to locate a clinical trial site near you.

Locate a clinical trial site

Get Involved

To determine whether your patient may qualify to participate in either the ACTIVATE or ACTIVATE-T clinical trial and to find clinical trial sites near you:

Contact Agios Medical Information

medinfo@agios.com
1-833-228-8474

About the Sponsor

Agios is focused on discovering and developing novel investigational medicines to treat cancer and rare genetic diseases through scientific leadership in the field of cellular metabolism. In addition to an active research and discovery pipeline across both therapeutic areas, Agios has multiple first-in-class investigational medicines in clinical and/or preclinical development. All Agios programs focus on genetically identified patient populations, leveraging our knowledge of metabolism, biology and genomics.

o For more information, please visit the company’s website at www.agios.com.