Mitapivat phase 3 data clinically meaningful for children 1 to <17 years with pyruvate kinase

Mitapivat phase 3 data clinically meaningful for children 1 to <17 years with pyruvate kinase | Image Credit: © MdBabul - © MdBabul - stock.adobe.com.

Topline results from the phase 3 ACTIVATE-KidsT study (NCT05144256) of mitapivat (Agios Pharmaceuticals) among children aged 1 to younger than 17 years with pyruvate kinase (PK) deficiency who are regularly transfused have been announced by Agios Pharmaceuticals.^1,2

The primary endpoint of transfusion reduction response (TRR) was defined as, "≥33% reduction in the total red blood cell transfusion volume from week 9 through week 32 of the double-blind period normalized by weight and actual study drug duration compared with the historical transfusion volume standardized by weight and to 24 weeks," according to the press release.

"The analysis of the primary endpoint was based on Bayesian statistical methodology whereby the TRR data from the adult ACTIVATE-T study inform and contribute to the analysis of TRR in the ACTIVATE-KidsT study," stated Agios. "The analysis was performed using a range of relative weights of borrowing from the adult ACTIVATE-T study, representing the prior degree of belief in the similarity of the treatment effect in the pediatric and adult populations."

The prespecified statistical criterion for the primary endpoint in the trail was not met with low or moderate borrowing weights from the ACTIVATE-T study (NCT03559699) in adults, though observed results were clinically meaningful.¹

In the ACTIVATE-KidsT study, 49 participants aged 1 to younger than 18 years were enrolled, with 32 randomized to twice-daily mitapivat and 17 to placebo. Nine of 32 (28.1%) patients in the mitapivat arm achieved a TRR compared to 11.8% of patients in the placebo arm.¹

A higher proportion of mitapivat patients compared to placebo patients achieved the secondary endpoints of transfusion-free response and normal hemoglobin response. Defined as no red blood cell transfusions from week 9 through week 32 of the double-blind period, 6 patients (18.8%) in the mitapivat arm had a transfusion-free response compared to 0 patients in the placebo arm.

There were 4 patients in the mitapivat arm who achieved a normal hemoglobin response compared to 0 in the placebo arm. Normal hemoglobin response was defined as "hemoglobin concentrations within normal limits at least once, 8 weeks or more after a transfusion, from Week 9 through Week 32 of the double-blind period," according to Agios.

“The ACTIVATE-KidsT trial is the first study of mitapivat in children who are regularly transfused and demonstrates the potential for meaningful clinical benefit, resolving the anemia and need for transfusions in a subset of children," said Rachael F. Grace, MD, MMSc, Dana-Farber/Boston Children’s Cancer and Blood Disorder Center, Harvard Medical School, Boston, Massachusetts, in a statement.¹

Agios has completed enrollment in the ACTIVATE-Kids study of mitapivat in children with PK deficiency who are not regularly transfused. Topline data is expected in 2025.

“After years of working with the PK deficiency community and caregivers whose children have no disease-modifying therapies, it is gratifying to share encouraging efficacy and safety data that may support the potential of a first-ever pediatric treatment for this rare blood disorder,” Sarah Gheuens, M.D., Ph.D., chief medical officer and head of R&D at Agios said in a statement.¹

"We look forward to completing our pediatric PK deficiency clinical development program next year with the readout of the ACTIVATE-Kids study of mitapivat in children who are not regularly transfused. More broadly, the ACTIVATE-KidsT study represents Agios’ first pediatric data readout. With our focus on lifelong, debilitating rare diseases, we hope that this study will be the first of several pediatric studies to make a positive impact in the lives of children facing rare hemolytic anemias, including PK deficiency, thalassemia and sickle cell disease.”¹

No discontinuations were observed in the study, and in the 32-week double-blind treatment period, a similar proportion of patients had adverse events in both the treatment and placebo arms. Safety data in the pediatric study were consistent with the safety profile for mitapivat in adult patients with PK deficiency who are regularly transfused.¹

References:

1. Agios announces results from Phase 3 ACTIVATE-KidsT study of mitapivat in children with PK deficiency who are regularly transfused. Agios Pharmaceuticals. Press release. August 1, 2024. Accessed August 1, 2024. https://investor.agios.com/news-releases/news-release-details/agios-announces-results-phase-3-activate-kidst-study-mitapivat
2. A study to evaluate the efficacy and safety of mitapivat in pediatric participants with pyruvate kinase deficiency (PKD) who are regularly transfused, followed by a 5-year extension period (ACTIVATE-KidsT). ClinicalTrials.gov. Updated July 12, 2024. Accessed August 1, 2024. https://clinicaltrials.gov/study/NCT05144256
3. A study evaluating the efficacy and safety of AG-348 in regularly transfused adult participants with pyruvate kinase deficiency (PKD). ClinicalTrials.gov. Updated January 4, 2022. Accessed August 1, 2024. https://clinicaltrials.gov/study/NCT03559699