Extension Study of AG-348 in Adult Participants With Pyruvate Kinase Deficiency Previously Enrolled in AG-348-006 or AG348-C-007

Lead sponsor

Agios Pharmaceuticals, Inc. is the lead sponsor of 52 studies on the registry; 6 are open to participants now.

Of its 23 completed or terminated interventional studies of FDA-regulated products, 4 (17%) have results posted.

Study arms

• Experimental
  Cohort 1

  Participants who received placebo in Study AG348-C-006 and met the eligibility criteria of this extension study were enrolled to receive mitapivat tablets, 5 milligrams (mg), twice daily (BID), administered orally, for 4 weeks as a starting dose, followed by two potential sequential dose level increases to 20 mg and 50 mg BID at Weeks 4 and 8 respectively as determined by the investigator based on safety and efficacy. The optimized dose for each participant was determined at Week 12, and participants then received that optimized dose for a period of 12 weeks (Weeks 13-24) as a fixed dose and from Week 25 to Week 193, until study withdrawal, or the study was closed.

  Drug: Mitapivat

• Experimental
  Cohort 2

  Participants who received mitapivat at a dose of 5 mg, 20 mg, or 50 mg, BID, in the fixed dose period of Study AG348-C-006 and met the eligibility criteria of this extension study continued to receive the same mitapivat dose up to Week 193 or until study withdrawal, or the study was closed.

  Drug: Mitapivat

• Experimental
  Cohort 3

  Participants who received mitapivat at a dose of 5 mg, 20 mg, or 50 mg, BID, in the fixed dose period of Study AG348-C-007 and met the eligibility criteria of this extension study continued to receive the same mitapivat dose up to Week 193 or until study withdrawal, or the study was closed.

  Drug: Mitapivat

Interventions

• DrugMitapivat

  Tablets

  Also known as: AG-348, AG-348 sulfate hydrate, Mitapivat sulfate

Primary outcomes

1. All Cohorts: Number of Participants With at Least One Treatment Emergent Adverse Events (TEAEs), Serious TEAEs, Related TEAEs and TEAEs With Severity Greater Than or Equal to Grade 3

   A clinical adverse event (AE) is any untoward medical occurrence in a participant or clinical investigation participant administered a pharmaceutical product and which does not necessarily have to have a causal relationship with the study drug. TEAEs are AEs with an initial onset date during the on-treatment period or worsening from baseline and include both serious and non-serious TEAEs. Severity of AEs was evaluated using the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE; Version 4.03): grade 1: mild; grade 2: moderate; grade 3: severe or medically significant but not immediately life-threatening; grade 4: life threatening or disabling; grade 5: death related to AE.

   Time frame: Up to 197 weeks

2. All Cohorts: Number of Participants With TEAEs Leading to Dose Reduction, Treatment Interruption and Treatment Discontinuation

   A clinical AE is any untoward medical occurrence in a participant or clinical investigation participant administered a pharmaceutical product and which does not necessarily have to have a causal relationship with the study drug. TEAEs are AEs with an initial onset date during the on-treatment period or worsening from baseline and include both serious and non-serious TEAEs. Number of participants with TEAEs leading to dose reduction, treatment interruption and treatment discontinuation are reported.

   Time frame: Up to 197 weeks

3. All Cohorts: Number of Participants With Clinically Significant Abnormalities in Laboratory Parameters Reported as Grade Greater Than or Equal to (≥)3 TEAEs

   Clinical laboratory assessments including hematology, clinical chemistry, triglycerides, urate, coagulation, urinalysis, and liver function tests were performed in the study. Clinically significant treatment-emergent laboratory abnormalities were graded according to the NCI CTCAE; Version 4.03: grade 1: mild; grade 2: moderate; grade 3: severe or medically significant but not immediately life-threatening; grade 4: life threatening or disabling; grade 5: death related to AE. Clinical significance was determined based on the judgment of the Investigator.

   Time frame: Up to 197 weeks

4. All Cohorts: Number of Participants With Clinically Significant Abnormalities in Vital Signs Measurements and Physical Examinations Reported as TEAEs

   Vital signs and physical examinations including height, weight, body mass index (BMI), systolic blood pressure, diastolic blood pressure, pulse rate, temperature were assessed. Number of participants who experienced clinically significant abnormalities in vital signs and physical examinations as TEAEs were reported. Clinical significance was determined based on the judgment of the Investigator.

   Time frame: Up to 197 weeks

5. All Cohorts: Number of Participants With Clinically Significant Abnormalities in Bone Mineral Density (BMD)

   BMD was measured by dual-energy X-ray absorptiometry (DXA) scans during the study. Number of participants with clinically significant abnormalities were reported. Clinical significance was determined based on the judgment of the Investigator.

   Time frame: Up to 192 weeks

6. All Cohorts: Change From Baseline in Adjusted Spine T-score

   T-score of adjusted spine were assessed by DXA scans. The T-score is the number of standard deviations that bone density is above or below the average. A score of ≥ -1 indicates normal bone density; score between \< -1 and \> -2.5 indicates a sign of osteopenia (bone density below normal), and score of ≤ -2.5 indicates a sign of osteoporosis.

   Time frame: Baseline, Week 192

7. All Cohorts: Change From Baseline in Adjusted Spine Z-score

   The Z-score is a statistical measure to describe whether a value was above or below the standard. A Z-score of 0 is equal to the standard. Lower numbers indicate values lower than the standard and higher numbers indicate values higher than the standard.

   Time frame: Baseline, Week 192

8. All Cohorts: Change From Baseline in Femoral Total T-score

   T-score of femoral total were assessed by DXA scans. The T-score is the number of standard deviations that bone density is above or below the average. A score of ≥ -1 indicates normal bone density; score between \< -1 and \> -2.5 indicates a sign of osteopenia (bone density below normal), and score of ≤ -2.5 indicates a sign of osteoporosis.

   Time frame: Baseline, Week 192

9. All Cohorts: Change From Baseline in Femoral Total Z-score

   The Z-score is a statistical measure to describe whether a value was above or below the standard. A Z-score of 0 is equal to the standard. Lower numbers indicate values lower than the standard and higher numbers indicate values higher than the standard.

   Time frame: Baseline, Week 192

10. All Cohorts: Number of Participants With Clinically Significant Abnormalities in Electrocardiogram (ECG) Parameters Reported as TEAEs

    The following ECG parameters including RR, PR, heart rate-corrected QT interval using the Fridericia's formula (QRS), QT, and QTc were assessed during the study. Number of Participants with clinically significant abnormalities in ECG parameters as TEAEs were reported. Clinical significance was determined based on the judgment of the Investigator.

    Time frame: Up to 197 weeks

Secondary outcomes

1. Cohort 1: Percentage of Participants Who Achieved a Hemoglobin (Hb) Response

   The Hb response was defined as a greater than or equal to (≥)1.5 grams per deciliter (g/dL) (0.93 millimoles per liter \[mmol/L\]) increase in Hb concentration from baseline that is sustained at 2 or more scheduled assessments, excluding those within 2 months (61 days) of transfusion. The baseline value for cohort 1 participants was the average of all available measurements from the central laboratory within 45 (42+3) days before start of study treatment in study AG348-C-011, excluding values within 61 days after a transfusion, or the baseline value from study AG348-C-006 if no assessment is available.

   Time frame: Baseline up to Week 24

2. Cohort 1: Average Change From Baseline in Hb Concentration at Weeks 16, 20, and 24

   The baseline value for participants was the average of all available measurements from the central laboratory within 45 (42+3) days before start of study treatment in study AG348-C-011, excluding values within 61 days after a transfusion, or the baseline value from study AG348-C-006 if no assessment is available. The mean of average change from baseline in Hb concentration across Weeks 16, 20 and 24 is reported.

   Time frame: Baseline, Weeks 16, 20, and 24

3. Cohort 1: Area Under the Plasma Concentration-Time Curve From Time Zero to 8-hours Post-dose (AUC0-8) of Mitapivat

   Time frame: Pre-dose, 0.5, 1, 2, 4, and 8 hours post-dose at Week 12

4. Cohort 1: Area Under the Plasma Concentration-Time Curve From Time Zero to Last Quantifiable Concentration (AUC0-last) of Mitapivat

   Time frame: Pre-dose, 0.5, 1, 2, 4, and 8 hours post-dose at Week 12

5. Cohort 1: Maximum Observed Plasma Concentration (Cmax) of Mitapivat

   Time frame: Pre-dose, 0.5, 1, 2, 4, and 8 hours post-dose at Week 12

6. Cohort 1: Time to Reach Maximum Observed Plasma Concentration (Tmax) of Mitapivat

   Time frame: Pre-dose, 0.5, 1, 2, 4, and 8 hours post-dose at Week 12

7. Cohort 1: Time of Last Quantifiable Concentration (Tlast) of Mitapivat

   Time frame: Pre-dose, 0.5, 1, 2, 4, and 8 hours post-dose at Week 12

8. Cohort 1: Plasma Concentration (Ctrough) at the End of a Dosing Interval of Mitapivat

   Time frame: Pre-dose, 0.5, 1, 2, 4, and 8 hours post-dose at Week 12

9. Cohort 1: Exposure-response (E-R) Relationship Between Safety Parameters and Mitapivat Concentration and Relevant Mitapivat Pharmacokinetic Parameters

   Time frame: First dose to up to 24 weeks

10. Cohorts 1 and 2: Change From Baseline in Hb Concentration

    The baseline value for cohort 1 participant was the average of all available measurements from the central laboratory within 45 (42+3) days before start of study treatment in study AG348-C-011, excluding values within 61 days after a transfusion, or the baseline value from study AG348-C-006 if no assessment was available. The baseline value for cohort 2 was from Study AG348-C-006.

    Time frame: Baseline, Week 192

11. Cohorts 1 and 2: Change From Baseline in Indirect Bilirubin

    The baseline value for cohort 1 participant was the average of all available measurements from the central laboratory within 45 (42+3) days before start of study treatment in study AG348-C-011, excluding values within 61 days after a transfusion, or the baseline value from study AG348-C-006 if no assessment is available. The baseline value for cohort 2 was from Study AG348-C-006.

    Time frame: Baseline, Week 192

12. Cohorts 1 and 2: Change From Baseline in Lactate Dehydrogenase (LDH)

    The baseline value for cohort 1 participant was the average of all available measurements from the central laboratory within 45 (42+3) days before start of study treatment in study AG348-C-011, excluding values within 61 days after a transfusion, or the baseline value from study AG348-C-006 if no assessment was available. The baseline value for cohort 2 was from Study AG348-C-006.

    Time frame: Baseline, Week 192

13. Cohorts 1 and 2: Change From Baseline in Haptoglobin Levels

    The baseline value for Cohort 1 participant was the average of all available measurements from the central laboratory within 45 (42+3) days before start of study treatment in study AG348-C-011, excluding values within 61 days after a transfusion, or the baseline value from study AG348-C-006 if no assessment was available. The baseline value for Cohort 2 was from Study AG348-C-006.

    Time frame: Baseline, Week 192

14. Cohorts 1 and 2: Change From Baseline in Reticulocytes/Erythrocytes Ratio

    The baseline value for Cohort 1 participants was the average of all available measurements from the central laboratory within 45 (42+3) days before start of study treatment in study AG348-C-011, excluding values within 61 days after a transfusion, or the baseline value from study AG348-C-006 if no assessment was available. The baseline value for Cohort 2 was from Study AG348-C-006.

    Time frame: Baseline, Week 192

15. Cohort 3: Change From Baseline in Number of Transfusion Episodes

    Number of transfusions at baseline was determined based on the transfusion data during the 52 weeks before informed consent for Cohort 3. Number of on-study transfusions was based on transfusions collected up to the end of the fixed dose period and standardized to 52 weeks. The change from baseline in number of transfusions was summarized for Cohort 3.

    Time frame: Baseline, Week 192

16. Cohort 3: Change From Baseline in Number of Red Blood Cell (RBC) Units Transfused

    Annualized total number of RBC units transfused (units/52-week) during the study, including data up to end of study (EOS), was the total number of RBC units transfused during the entire study\*52 / \[(date of EOS - date of start of study treatment + 1)/7\]. Number of RBC units were determined based on the transfusion data during the 52 weeks before informed consent of the antecedent study for Cohort 3. Number of on-study RBC units was based on transfusion data collected up to the end of the fixed dose period and standardized to 52 weeks.

    Time frame: Baseline, Week 192

17. All Cohorts: Change From Baseline in Health-Related Quality of Life (HRQoL) Patient-Reported Outcome (PRO) Scores: Pyruvate Kinase Deficiency Diary (PKDD)

    The PKDD is a validated, daily 7-item PRO instrument with a recall period of 24 hours that measures the core signs and symptoms associated with pyruvate kinase deficiency in adults. The symptoms include tiredness, jaundice, bone pain, shortness of breath, and energy level. PKDD daily scores were calculated based on the participant's response to the PKDD questionnaire. Score ranges from 25 to 76, with higher scores indicating more severe symptoms and a higher disease burden. The change from baseline in weekly mean scores was summarized. A negative change from baseline indicates a lower disease burden. Baseline of weekly mean score was defined as average of daily scores collected within 7 days before start of study treatment (mitapivat). For Cohort 1, last measurement before the start of study treatment in AG348-C-011 was used as baseline; if baseline was missing, then baseline value from AG348-C-006 was used. For Cohorts 2 \& 3 baseline values from -006 and-007, respectively, were used.

    Time frame: Baseline, Week 24

18. All Cohorts: Change From Baseline in HRQoL PRO Scores: Pyruvate Kinase Deficiency Impact Assessment (PKDIA)

    PKDIA is a 12-item PRO measure of common impacts of PK deficiency on activities of daily living. Participants rated how PK deficiency has impacted aspects of daily living in past 7 days, including impacts on relationships \& leisure and social, mental, and physical activities. PKDIA score at each visit was based on 8 items that were retained after in-trial psychometric validation and calculated at each visit based on participant's response to PKDIA questionnaire. Score ranges from 30 to 76, with higher scores indicating higher disease burden. Negative change from baseline indicates lower disease burden. Baseline was defined as the last complete assessment (with no missing item in response) before start of study treatment. For Cohort 1, last measurement before start of study treatment in AG348-C-011 was used as baseline; if baseline was missing, then baseline value from AG348-C-006 was used. For Cohorts 2 and 3, the baseline values from 006 and 007, respectively, were used.

    Time frame: Baseline, Week 24

Baseline characteristics

Publications

• van Beers EJ, Al-Samkari H, Grace RF, Barcellini W, Glenthoj A, DiBacco M, Wind-Rotolo M, Xu R, Beynon V, Patel P, Porter JB, Kuo KHM. Mitapivat improves ineffective erythropoiesis and iron overload in adult patients with pyruvate kinase deficiency. Blood Adv. 2024 May 28;8(10):2433-2441. doi: 10.1182/bloodadvances.2023011743. PubMed 38330179 ↗
• Rab MAE, Van Oirschot BA, Kosinski PA, Hixon J, Johnson K, Chubukov V, Dang L, Pasterkamp G, Van Straaten S, Van Solinge WW, Van Beers EJ, Kung C, Van Wijk R. AG-348 (Mitapivat), an allosteric activator of red blood cell pyruvate kinase, increases enzymatic activity, protein stability, and ATP levels over a broad range of PKLR genotypes. Haematologica. 2021 Jan 1;106(1):238-249. doi: 10.3324/haematol.2019.238865. PubMed 31974203 ↗

Study documents

• Study protocol · Jul 19, 2022
• Statistical analysis plan · Sep 24, 2020

Documents are hosted by the registry — open the source record to download them.

Individual participant data

Plan to share: No