AG-348-C-006 in Not Regularly Transfused Subjects with PK Deficiency
Research type
Research Study
Full title
A Phase 3, Randomized, Double-Blind, Placebo-Controlled Study to Evaluate the Efficacy and Safety of AG-348 in Not Regularly Transfused Adult Subjects with Pyruvate Kinase Deficiency
IRAS ID
240773
Contact name
Mark Layton
Contact email
Sponsor organisation
Agios Pharmaceuticals, Inc
Eudract number
2017-003823-31
Clinicaltrials.gov Identifier
N/A,
Duration of Study in the UK
2 years, 0 months, 15 days
Research summary
Summary of Research
AG-348 is being studied as a possible treatment for pyruvate kinase deficiency, a rare blood disease. It is a genetic disease which means that it may be transferred from a parent to a child.
People with pyruvate kinase deficiency have a deficiency in a specific protein (or enzyme, called “pyruvate kinase R”, PKR) that is needed to maintain healthy red blood cells. Red blood cells are essential for carrying oxygen to the tissues throughout the body and keeping us healthy. Because of this deficiency, patients with pyruvate kinase deficiency have fewer healthy red blood cells which causes fatigue, jaundice and sometimes difficulty breathing. Patients may require regular blood transfusions. There is no known cure for pyruvate kinase deficiency.
The study drug being tested in this study, AG-348, is a chemical that attaches to the PKR protein to increase the activity of this protein which allows the red blood cells to make more energy therefore helping the body to maintain normal red blood cells. In an ongoing study in patients with PK deficiency who are not regularly transfused, approximately 40% of patients had clinically meaningful and sustained increases in haemoglobin, the main component of your blood cells.The study is a randomized, double blinded, placebo-controlled study.Study treatment will be provided as tablets to be taken by mouth with water and with or without food. In order for the study to remain blinded, the tablets of AG-348 and the tablets of the placebo look exactly the same. At various times during the study, participants may be prescribed different doses of study treatment.
Summary of Results
Summary of clinical study results Efficacy and Safety of Mitapivat in Adults With Pyruvate Kinase (PK) Deficiency Who Were Not Regularly Receiving Transfusions (ACTIVATE) Protocol #: AG348-C-006 Study dates: August 2018 to October 2020
Thank you to the participants who took part in “A Study to Evaluate Efficacy and Safety of AG-348 in Adult Participants With PK Deficiency who are Not Regularly Transfused”.
This study helped researchers find out if a drug called mitapivat (also known as PYRUKYND or AG 348) could increase hemoglobin production in participants with PK deficiency who usually do not receive transfusions for the condition.
Why was this study done?
PK deficiency is a rare genetic blood disorder. It causes abnormal pyruvate kinase to form and affect the red blood cells. Pyruvate kinase is an important protein that helps red blood cells maintain the correct amount of energy. When this protein is not working properly, there can be a loss of red blood cells. PK deficiency can occur due to gene mutations. Gene mutations are abnormal changes in the structure of a gene. PKLR gene mutations can cause PK deficiency.
People who have PK deficiency may have symptoms such as fatigue, fast heartbeat, shortness of breath, bone pain, and yellowing of the skin and the whites of the eyes. Serious medical problems can occur, such as too much iron in the blood, gallstones, blood clots in the lungs, and weakened bones.
Before the study began, there were no approved medications to treat PK deficiency. Treatments available during the study were only able to help improve the symptoms of this condition and had not been developed specifically for PK deficiency. These treatments included blood transfusions, a process in which a donor’s blood is transferred into a patient’s body, to help restore healthy blood cells and increase hemoglobin levels.
Hemoglobin is a protein in red blood cells that carries oxygen from the lungs to cells in the body. After hemoglobin delivers oxygen, it then picks up carbon dioxide and carries it to the lungs to breathe out. Having enough oxygen in the cells is vital for a healthy body.
In this study, researchers wanted to see if mitapivat was able to increase the amount of hemoglobin in the blood of participants with PK deficiency.
They also wanted to see if mitapivat causes any side effects.
When was this study done?
This study started in August 2018 and ended in October 2020.
Who took part in this study?
Participants could take part if they:
• Were 18 years of age or older
• Were diagnosed with PK deficiency by a laboratory test
• Were not regularly receiving blood transfusions
• Had an average hemoglobin concentration of 100 grams per liter (g/L) or less
Normal hemoglobin is considered to be in the following ranges:
Adult men: 132 to 170 g/L
Adult women: 115 to 155 g/L.
Participants could not take part if they:
• Had a certain combination of PKLR gene mutations
• Had certain medical conditions
For more information on who could take part in this study, please refer to the websites listed at the end of this summary.
How many people took part in this study?
Altogether, 80 participants took part in this study, of whom 32 (40%) were male and 48 (60%) were female. Participants were between 18 and 78 years old.
The study took place at 46 clinics in Brazil, Canada, Denmark, France, Germany, Italy, Japan, the Netherlands, the Republic of Korea, Spain, Switzerland, Turkey, the United Kingdom, and the United States.
The list below shows how many participants were enrolled in each region.
• Western Europe: 39
• North America: 31
• Asia: 8
• Middle East: 1
• South America: 1
What happened during the study?
What did researchers want to know?
Researchers wanted to see how many participants had a 15 g/L or greater increase in hemoglobin that remained high 2 or more times when tested at Weeks 16, 20, and 24 of the study. This is referred to as a hemoglobin response. By comparison,1 bag of packed red blood cells can increase hemoglobin by about 10 g/L.
Researchers also collected information on any side effects possibly related to treatment with mitapivat.
What treatments were studied?
Researchers studied the following treatments that were taken by mouth:
• Mitapivat tablets
• Placebo tablets
A placebo is a treatment that looks like the study drug but does not contain any medication.
How was the study done?
There are many types of clinical studies. This study was:
• Phase 3: In a Phase 3 study, a drug is tested on a large number of participants.
• Randomized: Who received mitapivat and who received placebo was decided randomly by a computer program.
• Double-blind: Researchers and participants did not know which participants received mitapivat or placebo.
All participants had a physical exam to be sure they were a good fit before the study began. After the exam, they were placed randomly into either the mitapivat or placebo treatment group. Each group had a similar number of participants.
Participants received treatment in 2 periods, the dose optimization period and the fixed-dose period.
In the dose optimization period, the researchers wanted to determine what dose worked best for participants. Participants received 5 milligrams (mg) of mitapivat or placebo twice a day by mouth as a starting dose. This could be increased to 20 to 50 mg twice a day depending on how the participants responded to treatment.
After 12 weeks of dose optimization, participants received mitapivat or placebo twice daily for another 12 weeks during the fixed-dose period. The fixed dose was the ideal dose determined in the earlier dose optimization period.
One participant who signed up for this study left the study and did not receive any treatment. Because this participant left the study, only 39 participants received placebo while 40 participants received mitapivat.
All participants had checkup visits during treatment and 28 days after they stopped treatment. Researchers used laboratory and other medical tests to evaluate the safety of mitapivat and how much benefit it provided. Participants who discontinued treatment had their doses gradually reduced for safety. Researchers also recorded any side effects.
What were the results?
The study was completed as planned.
Sixteen participants (40%) in the mitapivat group had a 15 g/L or greater increase in hemoglobin that remained high 2 or more times when tested at Weeks 16, 20, and 24 of the study. No participants in the placebo group had a hemoglobin response.
For more information on study results, please refer to the websites listed at the end of this summary.
Were there any side effects?
Side effects are unwanted medical problems thought to be caused by a medicine or medical treatment.
Participants who receive a placebo can experience side effects that are sometimes caused by the participant’s expectations about treatment. Side effects may also be caused by something other than the placebo.
Not all of the participants in this study had side effects. One participant who signed up for the study did not receive treatment. As a result, side effects are presented here for 79 participants. A side effect is called serious when it is life-threatening, causes lasting problems, or needs hospital care.
The summary of treatment-related side effects for each group is shown below.
Placebo group - 39 participants
14 participants (36%) had side effects.
No participants had serious side effects.Mitapivat group - 40 participants
23 participants (58%) had side effects.
1 participant (3%) had serious side effects.One of the participants (3%) who had side effects in the mitapivat group experienced body aches as a serious side effect.
Common side effects that were reported in more than 10% of participants in either group were nausea and headache.
The number of participants in each group who had these common side effects are listed below.
Placebo group - 39 participants
4 participants (10%) had nausea.
6 participants (15%) had headaches.Mitapivat group - 40 participants
7 participants (18%) had nausea.
5 participants (13%) had headaches.
No participants died during the study or left the study early because of side effects.
How has this study helped patients and researchers?
Researchers look at the results of many studies to decide which medicines work and are safe for patients. This summary gives the results for 80 participants in a single study. The results of this study were helpful in making mitapivat available to adults with PK deficiency in the USA. Other studies may have more participants and may give different results.
Researchers may use the findings from this study to design other studies to learn whether mitapivat can help patients with PK deficiency.
Are there plans for further studies?
Clinical studies with mitapivat are ongoing, and further studies are planned. Further studies for pediatric participants are underway.
Where can I find out more about this study?
• Title of this Study: A Phase 3, Randomized, Double-Blind, Placebo-Controlled Study to Evaluate the Efficacy and Safety of AG-348 in Not Regularly Transfused Adult Subjects With Pyruvate Kinase Deficiency (ACTIVATE)
• Protocol Number: AG348-C-006
• EU Study Number: 2017-003823-31
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• US Study Number: NCT03548220
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East Midlands - Nottingham 2 Research Ethics Committee
REC reference
18/EM/0153
Date of REC Opinion
28 Aug 2018
REC opinion
Further Information Favourable Opinion