Mitapivat for Pyruvate Kinase Deficiency

(ACTIVATE-KidsT Trial)

Not currently recruiting at 25 trial locations

Overseen By Agios Medical Affairs

Age: < 18

Sex: Any

Trial Phase: Phase 3

Sponsor: Agios Pharmaceuticals, Inc.

Must be taking: Folic acid

Must not be taking: Hematopoietic stimulants, CYP3A4 inhibitors

Disqualifiers: Pregnancy, Malignancy, Cardiac disease, others

Pivotal Trial (Near Approval) This treatment is in the last trial phase before FDA approval

Prior Safety Data This treatment has passed at least one previous human trial

Compensation: Varies

Number of Visits: Unknown

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial tests the effectiveness and safety of a new treatment called mitapivat for children with pyruvate kinase deficiency (PK deficiency), a genetic disorder affecting red blood cells that often requires frequent blood transfusions. The study compares mitapivat to a placebo to determine if it can reduce the need for these transfusions. Children with PK deficiency who have needed 6 to 26 transfusions over the past year may be suitable candidates. As a Phase 3 trial, this study represents the final step before potential FDA approval, offering participants a chance to contribute to a treatment that could soon become widely available.

Will I have to stop taking my current medications?

The trial requires that you stop taking certain medications before participating. Specifically, you must stop taking strong inhibitors or inducers of CYP3A4, anabolic steroids, and any pyruvate kinase activators for a specified period before joining the study. You must also continue taking folic acid supplements during the study.

Is there any evidence suggesting that mitapivat is likely to be safe for pediatric participants with pyruvate kinase deficiency?

Research has shown that mitapivat is generally safe and well-tolerated in people with pyruvate kinase deficiency. In some studies, the most common serious side effects included hemolytic anemia (where red blood cells are destroyed faster than they are made) and pharyngitis (sore throat), each affecting about 4% of participants. About half of the participants experienced some side effects, though these were not always serious. Long-term safety data suggest that mitapivat could be a promising treatment for this condition. Overall, mitapivat has demonstrated a consistent safety profile across various studies, making it a potential option for those considering joining a clinical trial. ^{1 2 3 4 5}

Why do researchers think this study treatment might be promising for PK deficiency?

Mitapivat is unique because it directly targets the underlying cause of pyruvate kinase deficiency by activating the pyruvate kinase enzyme. Unlike the standard treatments, which often include regular blood transfusions and splenectomy to manage symptoms, mitapivat works at a cellular level to improve red blood cell energy metabolism. Researchers are excited about mitapivat because it offers a potentially transformative approach that could reduce or eliminate the need for more invasive and symptomatic treatments, offering a more sustainable and effective management option for patients.

What evidence suggests that mitapivat might be an effective treatment for pyruvate kinase deficiency?

Research has shown that mitapivat effectively treats pyruvate kinase deficiency. In previous studies, mitapivat significantly increased hemoglobin levels and reduced red blood cell breakdown in patients. About half of the adults treated with mitapivat experienced a quick rise in hemoglobin. Additionally, the treatment led to long-term improvements in symptoms and overall well-being. In this trial, participants will receive either mitapivat or a mitapivat-matching placebo at random. These findings suggest mitapivat could be a promising option for managing pyruvate kinase deficiency. ^{2 6 7 8 9}

Who Is on the Research Team?

Medical Affairs

Principal Investigator

Agios Pharmaceuticals, Inc.

Are You a Good Fit for This Trial?

This trial is for kids with Pyruvate Kinase Deficiency who need regular blood transfusions. They must be between 1-18 years old, not pregnant or breastfeeding, and without serious heart, liver, or kidney issues. Participants should have a history of receiving multiple transfusions and agree to use contraception if applicable.

Inclusion Criteria

Have complete records of transfusion history for the 52 weeks before providing informed consent/assent, defined as having all the following available: (1) all the transfusion dates, (2) the RBC transfusion volume (milliliters and/or number of units) for all the transfusions, and (3) hemoglobin concentrations within 1 week before transfusion for at least 80% of the transfusions

I have been taking folic acid for at least 21 days before starting the study drug and will continue during the study.

I have a confirmed genetic condition called pyruvate kinase deficiency.

Exclusion Criteria

I haven't had serious heart or lung problems or abnormal heart rhythms in the last 6 months.

Pregnant or breastfeeding

My genetic test shows I have specific mutations in the PKLR gene.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Dose Titration

Participants undergo an 8-week dose titration period to optimize dosing based on age and weight

8 weeks

Fixed-dose Treatment

Participants receive a fixed dose of mitapivat or placebo for 24 weeks

24 weeks

Open-label Extension

Participants who complete the double-blind period may continue receiving mitapivat in an open-label extension period

Up to 262 weeks

Follow-up

Participants are monitored for safety and effectiveness after treatment

4 weeks

What Are the Treatments Tested in This Trial?

Interventions

• Mitapivat
• Mitapivat-matching placebo

Trial Overview The study tests Mitapivat against a placebo in children with PKD who get regular transfusions. It's randomized (2:1 ratio), considering age and splenectomy status. After an initial period of dose adjustments followed by a fixed-dose period, participants may continue treatment for up to five years.

How Is the Trial Designed?

Group I: Mitapivat Experimental Treatment 2 Interventions

For participants randomized to receive mitapivat, dosing occurs orally twice daily (BID), and is based on age and weight. Dosing is optimized through 2 potential sequential increases in dose levels (1-5 mg, 4-20 mg and 10-50 mg) at Week 4 and Week 8, and aims to achieve the adult-equivalent exposure at 5, 20, and 50 mg. Following titration, participants remain on their individually optimized dose during the remainder of the Double-blind (DB) Period for 24 weeks. After the DB period, participants will enter an Open-label Extension (OLE) Period. To preserve blinding of treatment allocation, participants will continue mitapivat at their optimized dose and undergo mock titration with placebo for 8 weeks. At the conclusion of 8 weeks, participants may continue receiving mitapivat in the OLE Period for up to 262 weeks (including up to 2 weeks of dose taper).

Group II: Placebo Placebo Group 2 Interventions

For participants randomized to receive matched placebo, dosing is identical to that described above for mitapivat. Following the initial dose titration period, participants remain on their individually optimized dose during the remainder of the DB period for 32 weeks. After the DB period, participants will enter an OLE period. To preserve blinding of treatment allocation, participants will continue placebo at their optimized dose and undergo mitapivat dose optimization through 2 potential sequential increases in dose levels (1-5 mg, 4-20 mg and 10-50 mg) at Week 4 and Week 8 of the OLE Period, and aims to achieve the adult-equivalent exposure at 5, 20, and 50 mg. At the conclusion of 8 weeks, participants may continue receiving mitapivat in the OLE Period for up to 262 weeks (including up to 2 weeks of dose taper).

Who Is Running the Clinical Trial?

Agios Pharmaceuticals, Inc.

Lead Sponsor

Trials

55

Recruited

4,200+

Citations

1. nejm.org nejm.org/doi/full/10.1056/NEJMoa2116634

Mitapivat versus Placebo for Pyruvate Kinase Deficiency In patients with pyruvate kinase deficiency, mitapivat significantly increased the hemoglobin level, decreased hemolysis, and improved patient-reported ...

2. investor.agios.com investor.agios.com/static-files/af4512cc-c513-45ac-977a-49bccae1c139

Clinically meaningful improvements in patient‐reported ... Mitapivat, a first-in-class, oral activator of PK approved for adults with PK deficiency4 has demonstrated improvements in anemia and.

3. pubmed.ncbi.nlm.nih.gov pubmed.ncbi.nlm.nih.gov/31483964/

Safety and Efficacy of Mitapivat in Pyruvate Kinase Deficiency Conclusions: The administration of mitapivat was associated with a rapid increase in the hemoglobin level in 50% of adults with pyruvate kinase ...

4. ashpublications.org ashpublications.org/bloodrci/article/1/2/100014/546279/Long-term-mitapivat-treatment-is-safe-and

Long-term mitapivat treatment is safe and efficacious in ... Median of 2.53-year follow-up of mitapivat showed favorable safety and tolerability in patients with SCD. Sustained improvements in Hb, ...

5. onlinelibrary.wiley.com onlinelibrary.wiley.com/doi/full/10.1002/ajh.27312

Clinically meaningful improvements in patient‐reported ... Treatment with mitapivat showed long-term, durable, and clinically meaningful improvements in signs, symptoms, and functional impacts of PK ...

6. nejm.org nejm.org/doi/full/10.1056/NEJMoa1902678

Safety and Efficacy of Mitapivat in Pyruvate Kinase Deficiency The most common serious adverse events, hemolytic anemia and pharyngitis, each occurred in 2 patients (4%). A total of 26 patients (50%) had an ...

7. investor.agios.com investor.agios.com/news-releases/news-release-details/agios-announces-results-phase-3-activate-kidst-study-mitapivat

Agios Announces Results from Phase 3 ACTIVATE-KidsT ... In the 32-week double-blind treatment period, mitapivat was generally safe and well-tolerated, with safety results consistent with the safety ...

8. ashpublications.org ashpublications.org/blood/article/134/Supplement_1/3512/428360/Long-Term-Safety-and-Efficacy-of-Mitapivat-AG-348

Long-Term Safety and Efficacy of Mitapivat (AG-348), a ... These long-term data support the potential of mitapivat as the first disease-altering therapy for PK deficiency. Two phase 3 trials are underway ...

9. sciencedirect.com sciencedirect.com/science/article/abs/pii/S2352302622002149

Mitapivat in adult patients with pyruvate kinase deficiency ... Mitapivat was well tolerated across all doses studied in the ACTIVATE-T trial, and its safety profile was consistent across all previously reported studies.