Trial Outcomes & Findings for A Study Evaluating the Efficacy and Safety of AG-348 in Regularly Transfused Adult Participants With Pyruvate Kinase Deficiency (PKD) (NCT NCT03559699)

Last Updated: 2022-01-04

Results Overview

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.

Recruitment status

COMPLETED

Study phase

PHASE3

Target enrollment

27 participants

Primary outcome timeframe

From Part 2, Day 1 to Part 2 Week 24

Results posted on

2022-01-04

Participant Flow

A total of 27 participants were enrolled and treated in the study which was conducted across multiple sites in 9 countries: United States, Canada, Denmark, France, Ireland, Italy, Netherlands, Thailand, and United Kingdom. The study was conducted from 26 June 2018 to 12 November 2020.

Screening was done for a period of 8 weeks after the participant provided the informed consent. Investigators determined if the participants met all the inclusion criteria and none of the exclusion criteria to enroll in Part 1: Dose Optimization Period to receive AG-348 to determine the optimized dose followed by Part 2: Fixed Dose Period.

Participant milestones

Participant milestones
Measure	AG-348 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.
Overall Study STARTED	27
Overall Study COMPLETED	20
Overall Study NOT COMPLETED	7

Reasons for withdrawal

Reasons for withdrawal
Measure	AG-348 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.
Overall Study Withdrawal by Subject	6
Overall Study Lost to Follow-up	1

Baseline Characteristics

A Study Evaluating the Efficacy and Safety of AG-348 in Regularly Transfused Adult Participants With Pyruvate Kinase Deficiency (PKD)

Baseline characteristics by cohort

Baseline characteristics by cohort
Measure	AG-348 n=27 Participants Participants received AG-348 tablets, administered orally, at a starting dose of 5 mg, 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.
Age, Continuous	36.6 years STANDARD_DEVIATION 13.89 • n=5 Participants
Sex: Female, Male Female	20 Participants n=5 Participants
Sex: Female, Male Male	7 Participants n=5 Participants
Ethnicity (NIH/OMB) Hispanic or Latino	0 Participants n=5 Participants
Ethnicity (NIH/OMB) Not Hispanic or Latino	20 Participants n=5 Participants
Ethnicity (NIH/OMB) Unknown or Not Reported	7 Participants n=5 Participants
Race (NIH/OMB) American Indian or Alaska Native	0 Participants n=5 Participants
Race (NIH/OMB) Asian	3 Participants n=5 Participants
Race (NIH/OMB) Native Hawaiian or Other Pacific Islander	0 Participants n=5 Participants
Race (NIH/OMB) Black or African American	0 Participants n=5 Participants
Race (NIH/OMB) White	20 Participants n=5 Participants
Race (NIH/OMB) More than one race	0 Participants n=5 Participants
Race (NIH/OMB) Unknown or Not Reported	4 Participants n=5 Participants

PRIMARY outcome

Timeframe: From Part 2, Day 1 to Part 2 Week 24

Population: Full analysis set included all participants who received at least 1 dose of study drug.

Outcome measures

Outcome measures
Measure	AG-348 n=27 Participants Participants received AG-348 tablets, administered orally, at a starting dose of 5 mg, 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.
Percentage of Participants Achieving a Reduction in Transfusion Burden in Part 2	37 percentage of participants Interval 19.4 to 57.6

SECONDARY outcome

Timeframe: Part 1 Day 1 to Part 2 Week 24

Population: Full analysis set included all participants who received at least 1 dose of study drug.

The annualized total number of RBC units transfused during the entire study (both Part 1 and Part 2) is reported. It was calculated as the total number of RBC units transfused up to the end of Fixed Dose Period divided by the total number of days from the first dose date until the end date of Fixed Dose Period × 52.

Outcome measures

Outcome measures
Measure	AG-348 n=27 Participants Participants received AG-348 tablets, administered orally, at a starting dose of 5 mg, 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.
Annualized Number of RBC Units Transfused During the Study	11.52 RBC units Standard Deviation 10.543

SECONDARY outcome

Timeframe: From Part 2 Day 1 to Part 2 Week 24

Population: Full analysis set included all participants who received at least 1 dose of study drug. Number analyzed is the number of participants evaluated for the outcome measure.

This is the number of transfusion episodes in Part 2. The number of transfusion episodes were standardized to 24 weeks. Transfusions received over up to 3 consecutive days were counted as 1 episode.

Outcome measures

Outcome measures
Measure	AG-348 n=26 Participants Participants received AG-348 tablets, administered orally, at a starting dose of 5 mg, 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.
Number of Transfusion Episodes in Part 2	2.88 transfusion episodes Standard Deviation 2.694

SECONDARY outcome

Timeframe: From Part 2 Day 1 to Part 2 Week 24

Population: Full analysis set included all participants who received at least 1 dose of study drug.

Transfusion-free responders were the participants who were transfusion-free in Part 2.

Outcome measures

Outcome measures
Measure	AG-348 n=27 Participants Participants received AG-348 tablets, administered orally, at a starting dose of 5 mg, 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.
Percentage of Transfusion-Free Participants in Part 2	22.2 percentage of participants Interval 8.6 to 42.3

SECONDARY outcome

Timeframe: From Part 2 Day 1 to Part 2 Week 24

Population: Full analysis set included all participants who received at least 1 dose of study drug.

This is the percentage of participants who achieved hemoglobin (Hb) concentrations in the normal range at least once, 8 weeks or more after a transfusion in Part 2.

Outcome measures

Outcome measures
Measure	AG-348 n=27 Participants Participants received AG-348 tablets, administered orally, at a starting dose of 5 mg, 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.
Percentage of Participants Achieving Normal Hemoglobin (Hb) Concentrations in Part 2	11.1 percentage of participants Interval 2.4 to 29.2

SECONDARY outcome

Timeframe: Through 4 weeks after last dose (approximately Part 2, Week 31)

Population: Safety analysis set included all participants who received at least 1 dose of study drug.

An 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. An AE can, therefore, be any unfavorable and unintended sign (including an abnormal laboratory finding, for example), symptom, or disease temporally associated with the use of a medicinal product, whether or not considered related to the medicinal product.

Outcome measures

Outcome measures
Measure	AG-348 n=27 Participants Participants received AG-348 tablets, administered orally, at a starting dose of 5 mg, 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.
Percentage of Participants With Adverse Events	100 percentage of participants

OTHER_PRE_SPECIFIED outcome

Timeframe: From Part 1 Day 1 to end of Part 2, including follow-up (Day 197)

An AE is any unfavorable and unintended sign (including an abnormal laboratory finding, for example), symptom, or disease temporally associated with the use of a medicinal product, whether or not considered related to the medicinal product. An AESI can be serious or non-serious.

Outcome measures

Outcome data not reported

OTHER_PRE_SPECIFIED outcome

Timeframe: Part 1, Day 1, Part 2, Day 1 and Part 2, Week 24

Outcome measures

Outcome data not reported

OTHER_PRE_SPECIFIED outcome

Timeframe: Part 1, Day 1, Part 2, Day 1 and Part 2, Week 24

Outcome measures

Outcome data not reported

Adverse Events

AG-348

Serious events: 3 serious events

Other events: 27 other events

Deaths: 0 deaths

Serious adverse events

Serious adverse events
Measure	AG-348 n=27 participants at risk Participants received AG-348 tablets, administered orally, at a starting dose of 5 mg, 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.
Investigations Blood Triglyceride Increased	3.7% 1/27 • From Part 1 Day 1 to end of Part 2, including follow-up (up to Day 197) Safety analysis set included all participants who received at least 1 dose of the study drug.
Reproductive system and breast disorders Ovarian Cyst	3.7% 1/27 • From Part 1 Day 1 to end of Part 2, including follow-up (up to Day 197) Safety analysis set included all participants who received at least 1 dose of the study drug.
Renal and urinary disorders Renal Colic	3.7% 1/27 • From Part 1 Day 1 to end of Part 2, including follow-up (up to Day 197) Safety analysis set included all participants who received at least 1 dose of the study drug.

Other adverse events

Other adverse events
Measure	AG-348 n=27 participants at risk Participants received AG-348 tablets, administered orally, at a starting dose of 5 mg, 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.
Infections and infestations Nasopharyngitis	14.8% 4/27 • From Part 1 Day 1 to end of Part 2, including follow-up (up to Day 197) Safety analysis set included all participants who received at least 1 dose of the study drug.
Infections and infestations Upper respiratory tract infection	14.8% 4/27 • From Part 1 Day 1 to end of Part 2, including follow-up (up to Day 197) Safety analysis set included all participants who received at least 1 dose of the study drug.
Infections and infestations Viral upper respiratory tract infection	14.8% 4/27 • From Part 1 Day 1 to end of Part 2, including follow-up (up to Day 197) Safety analysis set included all participants who received at least 1 dose of the study drug.
Infections and infestations Influenza	7.4% 2/27 • From Part 1 Day 1 to end of Part 2, including follow-up (up to Day 197) Safety analysis set included all participants who received at least 1 dose of the study drug.
Infections and infestations Pharyngitis	7.4% 2/27 • From Part 1 Day 1 to end of Part 2, including follow-up (up to Day 197) Safety analysis set included all participants who received at least 1 dose of the study drug.
Infections and infestations Suspected COVID-19	7.4% 2/27 • From Part 1 Day 1 to end of Part 2, including follow-up (up to Day 197) Safety analysis set included all participants who received at least 1 dose of the study drug.
Gastrointestinal disorders Nausea	18.5% 5/27 • From Part 1 Day 1 to end of Part 2, including follow-up (up to Day 197) Safety analysis set included all participants who received at least 1 dose of the study drug.
Gastrointestinal disorders Vomiting	14.8% 4/27 • From Part 1 Day 1 to end of Part 2, including follow-up (up to Day 197) Safety analysis set included all participants who received at least 1 dose of the study drug.
Gastrointestinal disorders Abdominal pain	11.1% 3/27 • From Part 1 Day 1 to end of Part 2, including follow-up (up to Day 197) Safety analysis set included all participants who received at least 1 dose of the study drug.
Gastrointestinal disorders Diarrhoea	11.1% 3/27 • From Part 1 Day 1 to end of Part 2, including follow-up (up to Day 197) Safety analysis set included all participants who received at least 1 dose of the study drug.
Gastrointestinal disorders Dyspepsia	7.4% 2/27 • From Part 1 Day 1 to end of Part 2, including follow-up (up to Day 197) Safety analysis set included all participants who received at least 1 dose of the study drug.
Nervous system disorders Headache	37.0% 10/27 • From Part 1 Day 1 to end of Part 2, including follow-up (up to Day 197) Safety analysis set included all participants who received at least 1 dose of the study drug.
Nervous system disorders Dizziness	7.4% 2/27 • From Part 1 Day 1 to end of Part 2, including follow-up (up to Day 197) Safety analysis set included all participants who received at least 1 dose of the study drug.
Nervous system disorders Somnolence	7.4% 2/27 • From Part 1 Day 1 to end of Part 2, including follow-up (up to Day 197) Safety analysis set included all participants who received at least 1 dose of the study drug.
Investigations Alanine aminotransferase increased	37.0% 10/27 • From Part 1 Day 1 to end of Part 2, including follow-up (up to Day 197) Safety analysis set included all participants who received at least 1 dose of the study drug.
Investigations Aspartate aminotransferase increased	18.5% 5/27 • From Part 1 Day 1 to end of Part 2, including follow-up (up to Day 197) Safety analysis set included all participants who received at least 1 dose of the study drug.
Investigations Liver iron concentration increased	7.4% 2/27 • From Part 1 Day 1 to end of Part 2, including follow-up (up to Day 197) Safety analysis set included all participants who received at least 1 dose of the study drug.
Respiratory, thoracic and mediastinal disorders Dyspnoea	14.8% 4/27 • From Part 1 Day 1 to end of Part 2, including follow-up (up to Day 197) Safety analysis set included all participants who received at least 1 dose of the study drug.
Respiratory, thoracic and mediastinal disorders Oropharyngeal pain	11.1% 3/27 • From Part 1 Day 1 to end of Part 2, including follow-up (up to Day 197) Safety analysis set included all participants who received at least 1 dose of the study drug.
General disorders Fatigue	18.5% 5/27 • From Part 1 Day 1 to end of Part 2, including follow-up (up to Day 197) Safety analysis set included all participants who received at least 1 dose of the study drug.
Psychiatric disorders Initial insomnia	7.4% 2/27 • From Part 1 Day 1 to end of Part 2, including follow-up (up to Day 197) Safety analysis set included all participants who received at least 1 dose of the study drug.
Psychiatric disorders Middle insomnia	7.4% 2/27 • From Part 1 Day 1 to end of Part 2, including follow-up (up to Day 197) Safety analysis set included all participants who received at least 1 dose of the study drug.
Musculoskeletal and connective tissue disorders Back pain	14.8% 4/27 • From Part 1 Day 1 to end of Part 2, including follow-up (up to Day 197) Safety analysis set included all participants who received at least 1 dose of the study drug.
Reproductive system and breast disorders Vaginal haemorrhage	7.4% 2/27 • From Part 1 Day 1 to end of Part 2, including follow-up (up to Day 197) Safety analysis set included all participants who received at least 1 dose of the study drug.
Skin and subcutaneous tissue disorders Rash	11.1% 3/27 • From Part 1 Day 1 to end of Part 2, including follow-up (up to Day 197) Safety analysis set included all participants who received at least 1 dose of the study drug.
Metabolism and nutrition disorders Decreased appetite	7.4% 2/27 • From Part 1 Day 1 to end of Part 2, including follow-up (up to Day 197) Safety analysis set included all participants who received at least 1 dose of the study drug.

Additional Information

Medical Affairs

Agios Pharmaceuticals, Inc

Phone: 833-228-8474

Email: [email protected]

Results disclosure agreements

Principal investigator is a sponsor employee The information obtained from the clinical study will be used towards the development of AG-348 and may be disclosed to regulatory authority(ies), other Investigators, corporate partners, or consultants as required.
Publication restrictions are in place

Restriction type: OTHER