Satisfy: A Eurobloodnet Multicenter, Single-Arm Phase 2 Trial of Mitapivat in Adult Patients with Erythrocyte Membranopathies and Congenital Dyserythropoietic Anemia Type II - Results from the 8-Week Dose-Escalation Period

Background: Erythrocyte membranopathies, such as hereditary spherocytosis (HS) and dehydrated hereditary stomatocytosis (DHSt), represent a heterogeneous group of diseases characterized by hemolysis resulting from structural and functional defects in cytoskeletal, (trans)membrane and ion-channel proteins. Congenital dyserythropoietic anemia type II (CDA II) is another form of rare hereditary anemia characterized by ineffective erythropoiesis. Due to clinical similarities, along with concomitant membrane defects in CDA II, both diseases are difficult to distinguish by standard diagnostic methods. Current treatment options are mainly supportive, except for splenectomy, which is usually reserved for severe cases due to potential complications. Mitapivat is a first-in-class oral allosteric activator of pyruvate kinase (PK), a key glycolytic enzyme. Mitapivat enhances glycolysis, subsequently increasing ATP and reducing 2,3-diphosphoglycerate within the red blood cell. Previous pre-clinical studies in HS patients observed a relatively decreased PK activity, attributed to loss of membrane bound PK due to impaired structural integrity. Clinical trials evaluating mitapivat in other hemolytic anemias, including sickle cell disease and thalassemia, as well as in a mouse model of HS, have demonstrated efficacy by reducing hemolysis and increasing hemoglobin (Hb) concentration. Methods:This prospective, multicenter, single-arm phase 2 trial (NCT05935202) aims to evaluate the safety and efficacy of mitapivat in patients with erythrocyte membranopathies and CDA II. This study is being conducted in the Netherlands (NL) and Denmark (DK). Eligible subjects were adults (≥18 years) with a genetically supported (ACMG class 3-5), non-transfusion dependent erythrocyte membranopathy or CDA II, with an average Hb concentration of <11.0 g/dL for females and <13.0 g/dL for males. Key exclusion criteria were known history of PK deficiency, regularly scheduled blood transfusion episodes (≥5 in the past 12 months), and/or any significant medical condition. Here, we report data from all patients who completed the 8-week dose-escalation period. During this period, eligible subjects initially received mitapivat 50 mg twice daily (BID) for 4 weeks, followed by 100 mg BID, unless dose-limiting adverse events occurred. The primary endpoint was safety, as assessed by the occurrence of (serious) treatment-emergent adverse events (SAEs/TEAEs). Secondary endpoints included efficacy, defined as a Hb response of ≥1 g/dL compared to baseline, as well as change in hemolytic and erythropoietic markers. Statistical analyses were performed using R (Version 4.3.1). When appropriate, either paired sample t-test or a Wilcoxon signed-rank test was used. In this ongoing phase 2 trial, subjects tolerating mitapivat will continue in two consecutive 24-week fixed-dose periods. Results: As of July 2024, the study has enrolled 24 patients (16 HS, 4 CDA II and 4 DHSt). Of these, 18 patients (12 HS, 4 CDA II and 2 DHSt) completed the dose-escalation period, with a median age of 45 (range 24-79) years, 8/18 (44%) patients being female, and ethnic and racial backgrounds reflecting the patient population from DK and NL. All patients received the per-protocol doses of mitapivat, as no dose-limiting adverse events occurred. Safety analyses revealed mostly (50/51) mild (grade 1-2) TEAEs, with the majority (35/50) being transient. Most common reported TEAEs were headache (n=8, 16%), insomnia (n=8, 16%) and upper respiratory infection (n=7, 14%). One non-treatment related SAE (grade 3) occurred. Efficacy analyses showed a mean increase in Hb concentration of 1.0 g/dL (standard deviation ± 0.7 g/dL, p < 0.001), with11/18 (61%)patients reaching the efficacy endpoint of ≥1 g/dL increase (10 HS and 1 CDA II). Analyses of erythropoietic and hemolytic markers showed a significant mean decrease in reticulocytes (from 248 ± 177 at baseline to 183 ± 121 x 109/L at week 8, p < 0.001) and total bilirubin (from 3.3 ± 2.0 to 1.9 ± 0.8 mg/dL, p = 0.003) and a no change in LDH (from 216 ± 64 to 223 ± 69 U/L, p = 0.342). Conclusion: In the dose-escalation period of this phase 2 trial in patients with erythrocyte membranopathies and CDA II, mitapivat has showed initial improvements in hemoglobin and hemolytic markers, with a safety profile consistent with that observed in previous clinical trials. These findings support continued long-term evaluation.