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

• Sponsor: Agios Pharmaceuticals, Inc. (Industry)
• Overall Status: Completed
• CT.gov ID: NCT03559699
• Collaborator: (none)
• Enrollment: 27
• Locations: 19
• Arm: 1
• Actual Duration (Months): 28.6
• Patients Per Site: 1.4
• Patients Per Site Per Month: 0

Study Details

Study Description

Brief Summary

Study AG348-C-007 was a multicenter study designed to evaluate the efficacy and safety of treatment with AG-348 in a minimum of 20, with up to 40, participants with pyruvate kinase (PK) deficiency, who were regularly receiving blood transfusions. The study was composed of two parts. During Part 1, Dose Optimization Period, participants started on a dose of 5 mg AG-348 administered twice daily. Over the course of Part 1 each participant's dose of AG-348 was sequentially increased to 20 mg twice a day, followed by 50 mg twice a day depending on their tolerance. During Part 2, Fixed-Dose Period, participants received AG-348 at their optimized dose from Part 1.

Condition or Disease	Intervention/Treatment	Phase
Pyruvate Kinase Deficiency; Anemia, Hemolytic	Drug: AG-348	Phase 3

Study Design

• Study Type: Interventional
• Actual Enrollment: 27 participants
• Allocation: N/A
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: An Open-Label Study To Evaluate the Efficacy and Safety of AG-348 in Regularly Transfused Adult Subjects With Pyruvate Kinase (PK) Deficiency
• Actual Study Start Date: Jun 26, 2018
• Actual Primary Completion Date: Nov 12, 2020
• Actual Study Completion Date: Nov 12, 2020

Arms and Interventions

Arm	Intervention/Treatment
Experimental: 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.	Drug: AG-348; Part 1 (Dose Optimization Period): Participants began by receiving 5 mg orally, BID. Each participant's dose of AG-348 was sequentially increased to 20 mg BID followed by 50 mg BID depending on their response to AG-348 and their tolerance. Part 2 (Fixed Dose Period): Optimized dose determined in Part 1.

Outcome Measures

Primary Outcome Measures

1. Percentage of Participants Achieving a Reduction in Transfusion Burden in Part 2 [From Part 2, Day 1 to Part 2 Week 24]

   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.

Secondary Outcome Measures

1. Annualized Number of RBC Units Transfused During the Study [Part 1 Day 1 to Part 2 Week 24]

   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.

2. Number of Transfusion Episodes in Part 2 [From Part 2 Day 1 to Part 2 Week 24]

   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.

3. Percentage of Transfusion-Free Participants in Part 2 [From Part 2 Day 1 to Part 2 Week 24]

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

4. Percentage of Participants Achieving Normal Hemoglobin (Hb) Concentrations in Part 2 [From Part 2 Day 1 to Part 2 Week 24]

   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.

5. Percentage of Participants With Adverse Events [Through 4 weeks after last dose (approximately Part 2, Week 31)]

   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.

Other Outcome Measures

1. Percentage of Participants Experiencing an Adverse Event of Special Interest (AESI) [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.

2. Bone Mineral Density Z-Score [Part 1, Day 1, Part 2, Day 1 and Part 2, Week 24]

3. Bone Mineral Density T-Score [Part 1, Day 1, Part 2, Day 1 and Part 2, Week 24]

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years and Older
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion Criteria:

• Informed consent;

• Male or female, aged 18 or older;

• Presence of at least 2 mutant alleles in the Pyruvate Kinase Liver and RBC (PKLR) gene, of which at least 1 is a missense mutation;

• History of a minimum of 6 transfusion episodes in the 52-week period prior to date of informed consent;

• Complete records of transfusion history for the 52 weeks prior to the date of informed consent, including all transfusion dates, number of blood units transfused for all the transfusions, and Hb concentrations within 1 week prior to transfusion for at least 80% of the 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;

• Negative serum pregnancy test for women of reproductive potential;

• For women of reproductive potential as well as fertile men and their partners who are women of reproductive potential: be abstinent 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 AG-348;

• Willing to comply with all study procedures, in particular the individual transfusion trigger (TT) calculated based on 52 weeks of transfusion history, for the duration of the study.

Exclusion Criteria:

• Homozygous for the R479H mutation or have 2 non-missense mutations, without the presence of another missense mutation, in the PKLR gene;

• Significant medical condition that confers an unacceptable risk to participate in the study, and/or that could confound the interpretation of the study data;

• History of transfusions occurring on average more frequently than once every 3 weeks during the 52 weeks prior to date of informed consent;

• Splenectomy scheduled during the study treatment period or have undergone splenectomy within 12 months prior to signing informed consent;

• Currently enrolled in another therapeutic clinical trial. Prior participation in the PK Deficiency Natural History Study (NHS) (NCT02053480) or PK Deficiency Registry is permitted;

• Exposure to any investigational drug, device, or procedure within 3 months prior to the first dose of study drug;

• Prior bone marrow or stem cell transplant;

• Currently pregnant or breastfeeding;

• History of major surgery within 6 months of signing informed consent;

• Currently receiving medications that are strong inhibitors of CYP3A4, strong inducers of CYP3A4, strong inhibitors of P-glycoprotein (P-gp), or digoxin (a P-gp sensitive substrate medication) that have not been stopped for a duration of at least 5 days or 5 times their half-lives (whichever is longer) prior to start of study drug;

• Currently receiving hematopoietic stimulating agents (eg, erythropoietins [EPOs], granulocyte colony stimulating factors, thrombopoietins) that have not been stopped for a duration of at least 28 days prior to the first dose of study drug;

• History of allergy to sulfonamides if characterized by acute hemolytic anemia, drug induced liver injury, anaphylaxis, rash of erythema multiforme type or Stevens-Johnson syndrome, cholestatic hepatitis or other serious clinical manifestations;

• Allergy to AG-348 or its excipients;

• Currently receiving anabolic steroids, including testosterone preparations, within 28 days prior to the first dose of study drug.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	UCSF Benioff Children's Hospital	Oakland	California	United States	94609
2	Emory University	Atlanta	Georgia	United States	30322
3	Massachusetts General Hospital	Boston	Massachusetts	United States	02115
4	Seattle Cancer Care Alliance	Seattle	Washington	United States	98109
5	Toronto General Hospital, University Health Network	Toronto		Canada	M5G 2C4
6	University of Copenhagen, Herlev Hospital	Herlev		Denmark	2730
7	Hopital Universitaire Henri Mondor	Créteil		France	94010
8	Hôpital de la Timone	Marseille, Cedex 5		France	13385
9	St James's Hospital Department of Haematology	Dublin		Ireland
10	Fondazione IRCCS Ca' Granda, Ospedale Maggiore Policlinico	Milano		Italy	20122
11	AORN Cardarelli	Napoli		Italy	80131
12	Ospedale Galliera	Napoli		Italy	80131
13	AOU Policlinico, Università della Campania "Luigi Vanvitelli"	Napoli		Italy	80138
14	Universitair Medisch Centrum Utrecht	Utrecht		Netherlands	3584
15	Department of Paediatrics and Thalassaemia Center, Faculty of Medicine Siriraj Hospital, Mahidol University	Bangkok		Thailand	10700
16	Addenbrooke's Hospital	Cambridge		United Kingdom	CB2 0QQ
17	Imperial College Healthcare NHS Trust, Hammersmith Hospital	London		United Kingdom	W12 0NN
18	University College London	London		United Kingdom	WC1E 6BT
19	Manchester Royal Infirmary	Manchester		United Kingdom	M13 9WL

Sponsors and Collaborators

• Agios Pharmaceuticals, Inc.

Investigators

• Study Chair: Medical Affairs, Agios Pharmaceuticals, Inc.

Study Documents (Full-Text)

• Study Protocol - Mar 21, 2019
• Statistical Analysis Plan - Sep 25, 2020

More Information

Publications

None provided.

• Responsible Party: Agios Pharmaceuticals, Inc.
• ClinicalTrials.gov Identifier: NCT03559699
• Other Study ID Numbers: AG348-C-007; 2017-003803-22
• First Posted: Jun 18, 2018
• Last Update Posted: Jan 4, 2022
• Last Verified: Dec 1, 2021

• Individual Participant Data (IPD) Sharing Statement: No
• Plan to Share IPD: No
• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No
• Additional relevant MeSH terms: Anemia, Hemolytic, Congenital Nonspherocytic; Anemia, Hemolytic; Pyruvate Metabolism, Inborn Errors

Study Results

Participant Flow

Recruitment Details	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.
Pre-assignment Detail	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.

Arm/Group Title	AG-348
Arm/Group Description	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.
Period Title: Overall Study
STARTED	27
COMPLETED	20
NOT COMPLETED	7

Baseline Characteristics

Arm/Group Title	AG-348
Arm/Group Description	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.
Overall Participants	27
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	36.6 (13.89)
Sex: Female, Male (Count of Participants)
Female	20 74.1%
Male	7 25.9%
Ethnicity (NIH/OMB) (Count of Participants)
Hispanic or Latino	0 0%
Not Hispanic or Latino	20 74.1%
Unknown or Not Reported	7 25.9%
Race (NIH/OMB) (Count of Participants)
American Indian or Alaska Native	0 0%
Asian	3 11.1%
Native Hawaiian or Other Pacific Islander	0 0%
Black or African American	0 0%
White	20 74.1%
More than one race	0 0%
Unknown or Not Reported	4 14.8%

Outcome Measures

1. Primary Outcome

Title	Percentage of Participants Achieving a Reduction in Transfusion Burden in Part 2
Description	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.
Time Frame	From Part 2, Day 1 to Part 2 Week 24

Outcome Measure Data

Analysis Population Description

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

Arm/Group Title	AG-348
Arm/Group Description	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.
Measure Participants	27
Number (95% Confidence Interval) [percentage of participants]	37 137%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	AG-348
	Comments
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value	0.0002
	Comments	1-sided P-value
	Method	Binomial exact test
	Comments

2. Secondary Outcome

Title	Annualized Number of RBC Units Transfused During the Study
Description	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.
Time Frame	Part 1 Day 1 to Part 2 Week 24

Outcome Measure Data

Analysis Population Description

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

Arm/Group Title	AG-348
Arm/Group Description	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.
Measure Participants	27
Mean (Standard Deviation) [RBC units]	11.52 (10.543)

3. Secondary Outcome

Title	Number of Transfusion Episodes in Part 2
Description	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.
Time Frame	From Part 2 Day 1 to Part 2 Week 24

Outcome Measure Data

Analysis Population Description

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.

Arm/Group Title	AG-348
Arm/Group Description	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.
Measure Participants	26
Mean (Standard Deviation) [transfusion episodes]	2.88 (2.694)

4. Secondary Outcome

Title	Percentage of Transfusion-Free Participants in Part 2
Description	Transfusion-free responders were the participants who were transfusion-free in Part 2.
Time Frame	From Part 2 Day 1 to Part 2 Week 24

Outcome Measure Data

Analysis Population Description

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

Arm/Group Title	AG-348
Arm/Group Description	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.
Measure Participants	27
Number (95% Confidence Interval) [percentage of participants]	22.2 82.2%

5. Secondary Outcome

Title	Percentage of Participants Achieving Normal Hemoglobin (Hb) Concentrations in Part 2
Description	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.
Time Frame	From Part 2 Day 1 to Part 2 Week 24

Outcome Measure Data

Analysis Population Description

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

Arm/Group Title	AG-348
Arm/Group Description	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.
Measure Participants	27
Number (95% Confidence Interval) [percentage of participants]	11.1 41.1%

6. Secondary Outcome

Title	Percentage of Participants With Adverse Events
Description	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.
Time Frame	Through 4 weeks after last dose (approximately Part 2, Week 31)

Outcome Measure Data

Analysis Population Description

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

Arm/Group Title	AG-348
Arm/Group Description	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.
Measure Participants	27
Number [percentage of participants]	100 370.4%

7. Other Pre-specified Outcome

Title	Percentage of Participants Experiencing an Adverse Event of Special Interest (AESI)
Description	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.
Time Frame	From Part 1 Day 1 to end of Part 2, including follow-up (Day 197)

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title

Arm/Group Description

8. Other Pre-specified Outcome

Title	Bone Mineral Density Z-Score
Time Frame	Part 1, Day 1, Part 2, Day 1 and Part 2, Week 24

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title

Arm/Group Description

9. Other Pre-specified Outcome

Title	Bone Mineral Density T-Score
Time Frame	Part 1, Day 1, Part 2, Day 1 and Part 2, Week 24

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title

Arm/Group Description

Adverse Events

Time Frame	From Part 1 Day 1 to end of Part 2, including follow-up (up to Day 197)
Adverse Event Reporting Description	Safety analysis set included all participants who received at least 1 dose of the study drug.
Arm/Group Title	AG-348
Arm/Group Description	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.
All Cause Mortality
	AG-348
	Affected / at Risk (%)	# Events
Total	0/27 (0%)
Serious Adverse Events
	AG-348
	Affected / at Risk (%)	# Events
Total	3/27 (11.1%)
Investigations
Blood Triglyceride Increased	1/27 (3.7%)
Renal and urinary disorders
Renal Colic	1/27 (3.7%)
Reproductive system and breast disorders
Ovarian Cyst	1/27 (3.7%)
Other (Not Including Serious) Adverse Events
	AG-348
	Affected / at Risk (%)	# Events
Total	27/27 (100%)
Gastrointestinal disorders
Nausea	5/27 (18.5%)
Vomiting	4/27 (14.8%)
Abdominal pain	3/27 (11.1%)
Diarrhoea	3/27 (11.1%)
Dyspepsia	2/27 (7.4%)
General disorders
Fatigue	5/27 (18.5%)
Infections and infestations
Nasopharyngitis	4/27 (14.8%)
Upper respiratory tract infection	4/27 (14.8%)
Viral upper respiratory tract infection	4/27 (14.8%)
Influenza	2/27 (7.4%)
Pharyngitis	2/27 (7.4%)
Suspected COVID-19	2/27 (7.4%)
Investigations
Alanine aminotransferase increased	10/27 (37%)
Aspartate aminotransferase increased	5/27 (18.5%)
Liver iron concentration increased	2/27 (7.4%)
Metabolism and nutrition disorders
Decreased appetite	2/27 (7.4%)
Musculoskeletal and connective tissue disorders
Back pain	4/27 (14.8%)
Nervous system disorders
Headache	10/27 (37%)
Dizziness	2/27 (7.4%)
Somnolence	2/27 (7.4%)
Psychiatric disorders
Initial insomnia	2/27 (7.4%)
Middle insomnia	2/27 (7.4%)
Reproductive system and breast disorders
Vaginal haemorrhage	2/27 (7.4%)
Respiratory, thoracic and mediastinal disorders
Dyspnoea	4/27 (14.8%)
Oropharyngeal pain	3/27 (11.1%)
Skin and subcutaneous tissue disorders
Rash	3/27 (11.1%)

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

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.