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Maria Domenica Cappellini

Publications and source records attributed to Maria Domenica Cappellini.

2 recordsLinked to original sources
PubMed2026

Efficacy and safety of mitapivat in adults with transfusion-dependent α-thalassaemia or β-thalassaemia (ENERGIZE-T): a double-blind, randomised, multicentre, placebo-controlled, phase 3 trial.

BACKGROUND: The absence of disease-modifying therapies for patients with α-thalassaemia and oral disease-modifying therapies for patients with β-thalassaemia has been a substantial unmet need in these patients. We assessed the efficacy and safety of mitapivat, an oral allosteric activator of pyruvate kinase, in adults with transfusion-dependent thalassaemia. METHODS: ENERGIZE-T is a global, double-blind, randomised, placebo-controlled, phase 3 trial, conducted across 19 countries in North America, Europe, Asia-Pacific, South America, and the Middle East. Patients aged 18 years or older with transfusion-dependent α-thalassaemia or β-thalassaemia were randomly allocated (2:1) with a central interactive response technology system, stratified by geographical region and thalassaemia genotype, to receive 100 mg mitapivat or placebo orally twice a day for 48 weeks. The primary endpoint was transfusion reduction response (TRR), defined as a reduction of at least 50% in transfused red blood cell units with a reduction of at least two units in any consecutive 12-week period until week 48 compared with baseline. Efficacy was analysed in the full analysis set, comprising all randomly allocated patients. Type, severity, and relationship of adverse events and serious adverse events were assessed in patients who received at least one dose of study treatment. This study is registered with ClinicalTrials.gov (NCT04770779) and is active but not recruiting. FINDINGS: Between Nov 30, 2021 and May 2, 2023, 305 patients were screened, of whom 258 were randomly allocated (median age 33·5 years [IQR 27·0-44·0]; 136 [53%] female and 122 [47%] male participants). Of 258 patients allocated, 238 (92%) completed the double-blind treatment period. All patients were required to have a safety follow-up approximately 4 weeks after the final dose of study drug, regardless of completion of the double-blind period or continuation into the open-label extension period. In the full analysis set, TRRs occurred in 52 (30%) of 171 patients in the mitapivat group and 11 (13%) of 87 in the placebo group (adjusted difference 18 percentage points [95% CI 8-27]; two-sided p=0·0003). The safety analysis set comprised 172 patients in the mitapivat group (including one patient allocated to the placebo group who received one dose of mitapivat in error) and 85 in the placebo group. Adverse events were reported in 155 (90%) patients treated with mitapivat and 71 (84%) treated with placebo; the most common events with mitapivat were headache, upper respiratory tract infection, initial insomnia, diarrhoea, and fatigue. Serious adverse events were reported in 19 (11%) patients treated with mitapivat and 13 (15%) treated with placebo. Ten (6%) patients who received mitapivat and one (1%) who received placebo discontinued study treatment due to adverse events. No deaths were reported. INTERPRETATION: Mitapivat significantly reduced the transfusion burden and was generally well tolerated, showing a favourable benefit-risk profile. These findings support mitapivat as the first oral disease-modifying therapy for adults with transfusion-dependent α-thalassaemia or β-thalassaemia, providing a new treatment option to reduce transfusion burden in this patient population. FUNDING: Agios Pharmaceuticals, Inc.

Adult↗
PubMed2026

Exa-cel in Children with Transfusion-Dependent β-Thalassemia or Sickle Cell Disease.

BACKGROUND: Exagamglogene autotemcel (exa-cel) is a cell therapy in which autologous CD34+ hematopoietic cells are engineered through ex vivo clustered regularly interspaced short palindromic repeats-Cas9 editing of the erythroid-specific enhancer region of BCL11A to express fetal hemoglobin. In phase 3 studies involving participants 12 to 35 years of age with sickle cell disease or transfusion-dependent β-thalassemia, exa-cel eliminated vaso-occlusive crises and the need for red-cell transfusions. METHODS: In two ongoing, phase 3, open-label, single-group studies, we evaluated exa-cel in children 5 to 11 years of age with transfusion-dependent β-thalassemia or sickle cell disease. Before exa-cel infusion, participants underwent myeloablative conditioning with pharmacokinetically dose-adjusted busulfan. The primary end points were transfusion independence for at least 12 consecutive months in children with transfusion-dependent β-thalassemia and freedom from severe vaso-occlusive crises for at least 12 consecutive months in children with sickle cell disease. RESULTS: A total of 15 children with transfusion-dependent β-thalassemia and 11 with sickle cell disease received exa-cel; median follow-up was 16.0 months (range, 2.2 to 32.1) and 16.9 months (range, 7.6 to 33.1), respectively. Of 8 children with transfusion-dependent β-thalassemia who were followed to at least 16 months, 8 were transfusion independent; the status of the remaining 7 was not yet evaluable. Of 8 children with sickle cell disease who were followed to at least 16 months, 8 were free of vaso-occlusive crises; the status of the remaining 3 was not yet evaluable. All the children had at least one grade 3 or 4 adverse event; 2 children with transfusion-dependent β-thalassemia had severe veno-occlusive liver disease that was assessed as being related to busulfan conditioning, 1 of whom died. CONCLUSIONS: Exa-cel therapy resulted in transfusion independence or freedom from severe vaso-occlusive crises in participants with transfusion-dependent β-thalassemia or sickle cell disease, respectively, who were followed for at least 16 months. All the participants had grade 3 or 4 adverse events. (Funded by Vertex Pharmaceuticals and CRISPR Therapeutics; CLIMB THAL-141 ClinicalTrials.gov number, NCT05356195; CLIMB SCD-151 ClinicalTrials.gov number, NCT05329649.).

Child↗