Approval Probability
TA Base Rate
Adjusted LOA
ML Risk
AG-348 · 8 trials · 8 indications
Hemoglobin response (HR) is 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. The baseline Hb concentration is the average of all available Hb concentrations for a participant during the Screening Period up to the first dose of study treatment. As pre-specified in the protocol, the data for this outcome measure is summarized between the active arm vs the placebo arm (AG-348 5 mg, 20 mg and 50 mg arms are analyzed and reported together in comparison to Placebo).
Reduction in transfusion burden is defined as a ≥33% reduction in the number of RBC units transfused during the Fixed Dose Period standardized to 24 weeks compared with the historical transfusion burden standardized to 24 weeks (Standardized Control Period). The on-study (Fixed Dose Period) transfusion burden was calculated as the total number of transfused RBC units received in the Fixed Dose Period standardized to 24 weeks.
HR was defined as a ≥1.0 gram per deciliter (g/dL) increase in Hb concentration from Baseline at 1 or more assessments between Week 4 and Week 12 (inclusive). A participant's Baseline Hb concentration was defined as the average of all the participant's available Hb concentrations during the screening period up to the first dose of study drug.
An AE was defined as any untoward medical occurrence associated with the use of a drug in humans, whether or not considered study drug-related.
AG-348 Area Under the Curve
AG-348 Maximum Plasma Concentration
Incidence of adverse events and descriptive statistics for safety laboratory parameters, physical exam findings, vital signs and ECGs.
| Arm | Type | Description |
|---|---|---|
| Placebo | PLACEBO_COMPARATOR | Participants received a matching placebo to AG-348 tablets, for a period of 12 weeks as an optimized dose. This was followed by matching placebo further, for a period of 12 weeks as a fixed-dose. |
| AG-348, 5 mg | EXPERIMENTAL | Participants received AG-348 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 as 5 mg BID at Week 12, and participants then received that optimized dose for a period of 12 weeks as a fixed dose. |
| AG-348, 20 mg | EXPERIMENTAL | Participants received AG-348 tablets, 5 mg 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 as 20 mg BID at Week 12, and participants then received that optimized dose for a period of 12 weeks as a fixed dose. |
| AG-348, 50 mg | EXPERIMENTAL | Participants received AG-348 tablets, 5 mg 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 as 50 mg BID at Week 12, and participants then received that optimized dose for a period of 12 weeks as a fixed dose. |
| AG-348 | EXPERIMENTAL | Participants received AG-348 tablets, administered orally, at a starting dose of 5 milligrams (mg), twice daily (BID), followed by two sequential dose level increases to 20 mg and 50 mg BID, for a period of 16 weeks in Part 1. This was followed by optimized dose BID, as determined by the investigator in Part 1, for a period of 24 weeks in Part 2. |
| AG-348 50 mg BID | EXPERIMENTAL | Participants with Pyruvate Kinase (PK) deficiency will receive AG-348, 50 milligrams (mg), as initial dose, twice daily (BID) for 24 weeks (Core Period). Participants will be assigned to initial doses, however, over the course of the Core Period they will be treated across a range of doses due to treatment emergent adverse events (AEs) and hemoglobin (Hb) levels exceeding mid-point of sex-adjusted ranges. At the Week 24 visit, Core Period participants who have safely tolerated AG-348 and demonstrating clinical activity in response to AG-348 will be rolled over to the Extension Period. During the extension period, participants will continue to receive AG-348 50 mg, BID, for up to 102 months. |
| AG-348 300 mg BID | EXPERIMENTAL | Participants with PK deficiency will receive AG-348, 300 mg, as initial dose, BID for 24 weeks (Core Period). Participants will be assigned to initial doses, however, over the course of the Core Period they will be treated across a range of doses due to treatment emergent AEs and Hb levels exceeding mid-point of sex-adjusted ranges. At the Week 24 visit, Core Period participants who have safely tolerated AG-348 and demonstrating clinical activity in response to AG-348 will be rolled over to the Extension Period. During the extension period, participants will continue to receive AG-348 300 mg, BID, up to 102 months. |
| Cohort A | EXPERIMENTAL | - |
| Cohort B | EXPERIMENTAL | - |
| Cohort C | EXPERIMENTAL | - |
| Name | Type | Description |
|---|---|---|
| Placebo | DRUG | Placebo matching AG-348 tablets, administered to maintain the blind. |
| AG-348 | DRUG | AG-348 tablets. |
| [13C6]AG-348 | DRUG | IV microdose of approximately 100 micrograms (mcg), single dose. |
Inclusion Criteria: * Informed consent; * Male or female, aged 18 years or older; * Documented clinical laboratory confirmation of pyruvate kinase (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; * Hemoglobin ...
AG-348 is an investigational small molecule being developed by Agios Pharmaceuticals, Inc. (AGIO) as an activator of pyruvate kinase-R (PKR), an enzyme. It is being studied in early-stage clinical trials for conditions including thalassemia and pyruvate kinase deficiency, as well as in healthy volunteer studies.
AG-348 targets pyruvate kinase-R (PKR), an enzyme involved in red blood cell energy production. By activating this enzyme, the drug is being investigated for potential effects in conditions such as thalassemia and pyruvate kinase deficiency, though its efficacy in these diseases has not been established.
AG-348 is being developed by Agios Pharmaceuticals, Inc., a biopharmaceutical company traded on the NASDAQ under the ticker AGIO. The company is conducting Phase 1 clinical trials of this small molecule drug candidate.
AG-348 is in Phase 1 clinical development. All completed trials for the drug are Phase 1 studies, primarily in healthy volunteers. It is an investigational agent and has not been approved by regulatory authorities for any indication.
AG-348 has been studied in several Phase 1 clinical trials, including NCT02108106 and NCT02149966 in healthy volunteers, NCT03250598 in healthy Japanese and non-Asian subjects, and NCT03703505 in healthy male participants. All trials listed are completed, with one active trial ongoing.
AG-348 is also known as mitapivat, an investigational activator of pyruvate kinase-R being developed by Agios Pharmaceuticals. The drug is being studied in Phase 1 trials for conditions including thalassemia and pyruvate kinase deficiency, though it remains in clinical development.