AG-348-C-011 - Extension Study of AG-348 in Adult Subjects with PKD
Research type
Research Study
Full title
An Open-Label, Multicenter, Extension Study of AG-348 in Adult Subjects with Pyruvate Kinase Deficiency Previously Enrolled in AG-348 Studies
IRAS ID
258746
Contact name
Mark Layton
Contact email
Sponsor organisation
Agios Pharmaceuticals, Inc.
Eudract number
2018-003459-39
Clinicaltrials.gov Identifier
Duration of Study in the UK
5 years, 4 months, 1 days
Research summary
Summary of Research:
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.Study treatment will be provided as tablets to be taken by mouth with water and with or without food.
Research Summary:
Lay summary of study results: Why was this study done?
Pyruvate kinase (PK) deficiency is a rare blood disorder passed down from parents to children.
In people who have this condition, the PK protein does not form properly. When this protein is not working as it should, the red blood cells (RBCs) cannot make enough energy to survive for very long in the body. This means that there are less RBCs to carry oxygen around the body with the help of hemoglobin. Having fewer than normal RBCs in the blood is called anaemia.
People with this condition may have symptoms, such as tiredness, a fast heartbeat, shortness of breath, yellowing of the skin and eyes, and bone problems. They are also at risk of long-term problems such as too much iron in the blood (iron overload) and weakened bones.
When this study was designed, there were no approved medicines to treat this condition. It is commonly treated with blood transfusions, which may help improve the symptoms but does not treat the cause of the condition. However, repeated transfusions can lead to iron overload. This can damage the heart, liver, and cause hormone problems.The study medicine, mitapivat, also known as AG-348, is approved in some countries to treat PK deficiency in adults. It works by increasing the activity of the PK protein. This helps RBCs make more energy, allowing the cells to survive longer and carry oxygen more effectively throughout the body.
In this extension study, researchers wanted to learn about the long-term safety and effects of mitapivat in participants with PK deficiency who previously took part in earlier mitapivat studies.Who took part in this study?
Participants could take part if:
• They completed the entire treatment period in either of the previous mitapivat studies, AG348-C-006 or AG348-C-007 • The study doctors considered that participants who received mitapivat in the previous study benefited from the treatment Participants could not take part if:
• They developed any serious health problems or had abnormal lab results during the previous mitapivat study • They were planning to have a surgery to remove their spleen during the studyHow may people took part in this study?
Altogether, 90 participants took part in this study, of whom 35 (39%) were men and 55 (61%) were women.
Participants were between 18 and 78 years old.
The study took place at 42 clinics in 16 countries.What happened during the study?
Researchers wanted to know if taking mitapivat for a long time was safe and was well tolerated by participants. To do this, they looked closely at the number of participants who had:
• Side effects: They are unwanted medical problems that may or may not be caused by the study treatment.
Researchers rated side effects based on a standard scale called the Common Terminology Criteria for Adverse Events (CTCAE).
• Serious side effects. Side effects are called serious when they are fatal, life-threatening, cause lasting problems, or need hospital care.
• Side effects related to the study treatment • Side effects that caused the dose to be reduced.
• Side effects that caused treatment to be paused temporarily.
• Side effects that led to stopping the treatment completely.
• Clinically important changes in tests, including vital signs, laboratory tests, and electrocardiogram (ECG). An ECG is a test used to check the heart’s function.
• Measurements of bone strength in different areas of the body (such as the hip, upper thigh bone, and lower back) to determine if the bones are weaker or stronger than normal.
What treatments were studied?
Researchers studied the following treatment that was taken by mouth, twice a day:
• Mitapivat: 5, 20, or 50 milligrams (mg) tablets.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 in a large number of participants.
• Open label: This means that both the researchers and participants knew that all participants received mitapivat.
Participants were screened to make sure they were a good fit for this study. This screening happened at the same time as their last visit in the previous study (Study AG348-C-006 or Study AG348-C-007).
Participants were divided into 3 groups to receive mitapivat during this study based on their treatment in previous studies:
• Group 1: Participants who received a placebo in Study AG348-C-006. A placebo is a treatment that looks like the study drug but does not contain any medication.
• Group 2: Participants who received mitapivat in Study AG348-C-006.
• Group 3: Participants who received mitapivat in Study AG348-C-007.
Participants in Group 1 received treatment in 3 periods, the dose optimization period, fixed-dose period, and the continued treatment period.
• In the dose optimization period, researchers wanted to find the dose that worked best for participants. Participants received 5 mg of mitapivat twice a day. This dose could be increased up to 20 or 50 mg, twice a day, based on how well the treatment works and if there are any side effects.
• After 12 weeks of the dose optimization period, participants entered the fixed-dose period, which lasted for another 12 weeks. During this period, they continued taking mitapivat, twice a day at the dose that was found to work best for them during the earlier period.
• After 24 weeks, if the study doctor considered that participants received benefit from the treatment, they entered the continued treatment period. They continued mitapivat treatment at the same dose that they took at Week 24.
Participants in Groups 2 and 3, who had already been taking mitapivat in previous studies, continued receiving mitapivat at the same dose as in the previous study until Week 193.
All participants had checkup visits during treatment and 28 days after they stopped treatment.
Throughout this study, researchers checked participants’ vital signs, performed ECGs and lab tests, and closely monitored participants for safety.What were the results?
The study was completed as planned. The results are reported for all participants who received at least 1 dose of mitapivat.
What treatment-related serious side effects happened during the study?
There were 2 participants in Group 1 who had serious treatment-related side effects.
• 1 participant had a stomach and bowel infection (gastroenteritis).
• 1 participant had sudden uncontrolled movements (seizure).How has this study helped participants and researchers?
Researchers look at the results of many studies to decide which treatments work best and are safe for people. This summary gives the results for 90 participants in a single study.
Overall, the results showed that mitapivat was safe and well tolerated by participants with PK deficiency over 4 years of treatment.Where can I find out more about this study?
Title of this Study: An Open-Label, Multicenter, Extension Study of AG-348 in Adult Subjects With Pyruvate Kinase Deficiency Previously Enrolled in AG-348 Studies Protocol Number: AG348-C-011 EU Study Number: 2018-003459-39 US Study Number: NCT03853798 More information about this study can be found at
https://gbr01.safelinks.protection.outlook.com/?url=https%3A%2F%2Ftrack.pstmrk.it%2F3ts%2Fwww.agios.com%252Fpatients-caregivers%252Fclinical-trials%252F%2FNBTI%2FGLy_AQ%2FAQ%2F0c0269a8-3824-4748-b99a-48199f5aa0ae%2F1%2Fj53mH2OLbI&data=05%7C02%7Ctyneandwearsouth.rec%40hra.nhs.uk%7C27821069e9ef46e6857a08ddc5142db5%7C8e1f0acad87d4f20939e36243d574267%7C0%7C0%7C638883412633009282%7CUnknown%7CTWFpbGZsb3d8eyJFbXB0eU1hcGkiOnRydWUsIlYiOiIwLjAuMDAwMCIsIlAiOiJXaW4zMiIsIkFOIjoiTWFpbCIsIldUIjoyfQ%3D%3D%7C0%7C%7C%7C&sdata=foVVEK7qUP3tbfc1QOEUR4vcBjlPjWnpT9kv4YBjoEk%3D&reserved=0REC name
North East - Tyne & Wear South Research Ethics Committee
REC reference
19/NE/0137
Date of REC Opinion
12 Jun 2019
REC opinion
Further Information Favourable Opinion