ACTIVATE-Kids Study Demonstrates Efficacy of Oral Therapy for Children With PK Deficiency

Findings from the ACTIVATE-Kids study support the use of mitapivat (Pyrukynd; Agios Pharmaceuticals), an oral therapy, for children with pyruvate kinase (PK) deficiency who are not regularly transfused. The trial met its primary end point of hemoglobin response.¹

Mitapivat is a PK activator indicated for the treatment of hemolytic anemia in adults with PK deficiency.¹ Now, the new data could support an FDA application for its use in pediatric patients younger than 18 years.

Mitapivat is a PK activator | Image credit: © Suzi Media | stock.adobe.com

PK deficiency is a genetic disorder caused by changes in the PKLR gene, resulting in a deficiency of the PK enzyme. PK is involved in the process of turning glucose into adenosine triphosphate, and its deficiency results in a lack of red cell energy and premature hemolysis. Rather than lasting 120 days, the red blood cells of patients with PK deficiency last only a few days or weeks.²

Symptoms can vary significantly, from mild to life-threatening. In children and adults, the most common symptom is anemia, which can cause fatigue, weakness, dizziness, irritability, headaches, pale skin, dyspnea, and cardiac symptoms. Individuals with PK deficiency can also develop splenomegaly due to the spleen’s role in filtering out abnormal red blood cells.²

Importantly, PK deficiency can affect newborns, presenting as severe anemia and jaundice. Unlike in children and adults, elevated bilirubin levels in infants can lead to the neurological condition kernicterus, characterized by the accumulation of toxic levels of bilirubin. Aggressive treatment may be necessary to avoid the risk of kernicterus in newborns with PK deficiency.²

In August 2024, Agios Pharmaceuticals reported the first pediatric data readout from the ACTIVATE-Kids trial of mitapivat in children who are regularly transfused. According to a news release, 28.1% of participants in the mitapivat arm achieved the primary end point of transfusion reduction response, compared to 11.8% of participants in the placebo arm. Transfusion-free response and normal hemoglobin were only observed in patients in the mitapivat arm.³

“PK deficiency can lead to debilitating fatigue and a range of serious complications and symptoms, severely affecting and disrupting a child’s quality of life,” said Rachael F. Grace, MD, MMSc, an investigator in the ACTIVATE-Kids study, in a news release. “The efficacy and safety results from the ACTIVATE-Kids and ACTIVATE-KidsT phase 3 studies demonstrate the potential for clinically meaningful benefits with mitapivat in children with PK deficiency who are and are not regularly transfused, improving anemia and reducing the need for transfusions.”¹

According to the topline results from ACTIVATE-Kids, a total of 30 patients aged 1 to less than 18 years were enrolled, 19 of whom were randomized to mitapivat twice daily and 11 randomized to matched placebo. The primary end point of hemoglobin response was defined as a 1.5 g/dL or greater increase in hemoglobin concentration from baseline that is sustained at 2 or more scheduled assessments at weeks 12, 16, and 20 during the double-blind period.¹

Findings showed that 31.6% (n = 6) of the patients in the mitapivat arm achieved a hemoglobin response, compared with 0% (n = 0) of patients in the placebo arm (95% CI=10.8%-52.7%). Furthermore, improvements in baseline for markers of hemolysis (indirect bilirubin, lactate dehydrogenase, and haptoglobin) were observed only in the mitapivat arm. All patients in both treatment arms completed the 20-week double-blind period of the study.¹

During the double-blind period, a similar proportion of patients in both arms experienced adverse events (AEs). There were no discontinuations of study treatment due to AEs or for any reason.¹

“The positive results for the ACTIVATE-Kids phase 3 trial represent a very important step forward for the PK deficiency community, building on the clinical benefits demonstrated by mitapivat in adults with PK deficiency,” said Sarah Gheuns, MD, PhD, chief medical officer and head of research and development at Agios, in the news release. “With data now available from the randomized, placebo-controlled, double-blind period of both phase 3 pediatric PK deficiency studies, we look forward to sharing more detailed findings with the community and interacting with regulators.”¹

REFERENCES

1. Agios’ phase 3 ACTIVATE-Kids study of mitapivat in children with pyruvate kinase (PK) deficiency not regularly transfused met primary endpoint. News release. Agios Pharmaceuticals. February 13, 2025. Accessed February 14, 2025. https://investor.agios.com/news-releases/news-release-details/agios-phase-3-activate-kids-study-mitapivat-children-pyruvate

2. Pyruvate Kinase Deficiency. National Organization for Rare Disorders. Updated August 22, 2023. Accessed February 14, 2025. https://rarediseases.org/rare-diseases/pyruvate-kinase-deficiency/#symptoms

3. Agios announces results from phase 3 ACTIVATE-KidsT study of mitapivat in children with PK deficiency who are regularly transfused. News release. Agio Pharmaceuticals. August 1, 2024. Accessed February 14, 2025. https://investor.agios.com/news-releases/news-release-details/agios-announces-results-phase-3-activate-kidst-study-mitapivat