Mitapivat (also known as PYRUKYND), a pioneering oral drug, activates pyruvate kinase allosterically to enhance ATP production. It has the potential to alleviate metabolic stress, addressing thalassemia comprehensively and potentially reducing complications while improving health-related quality of life (HRQoL). Currently, there are no approved oral therapies for modifying β-thalassemia or any approved agents for α-thalassemia.

Results from the Phase III global ENERGIZE trial, presented at EHA 2024, included 194 adults with α- or β-non-transfusion-dependent thalassemias (NTDT) and baseline Hb ≤10 g/dL. Participants were randomized 2:1 to receive either mitapivat 100 mg twice daily or placebo over 24 weeks. 

The study successfully met its primary endpoint of hemoglobin response, with 42.3% of patients in the mitapivat group achieving an increase of ≥1.0 g/dL in average Hb concentration from Weeks 12 to 24, compared to 1.6% in the placebo group.

Demographics and baseline characteristics were balanced between the two treatment arms, reflecting the NTDT patient population. Hemoglobin response rates favored mitapivat across all prespecified subgroups, including different thalassemia genotypes and baseline Hb concentrations. Specifically, significant improvements were observed in patients with beta-thalassemia and those with lower baseline Hb concentrations.

Mitapivat treatment also showed statistically significant improvements in key secondary endpoints. The key secondary endpoint was change from baseline in average Functional Assessment of Chronic Illness Therapy–Fatigue Scale (FACIT-Fatigue) score from Week 12 through Week 24.  Adverse event (AE) incidence was similar between mitapivat and placebo groups, with the most common treatment-emergent adverse events being headache, initial insomnia, nausea, and upper respiratory tract infection. Grade ≥3 treatment-related adverse events were rare, and no serious adverse events were reported. Discontinuation due to adverse events occurred in a small percentage of patients in the mitapivat arm only.

These findings highlight mitapivat as a promising treatment option for NTDT, addressing both efficacy and safety concerns, with potential implications for improving patient outcomes and quality of life. Agios Pharmaceuticals has also reported encouraging outcomes from the Phase III ENERGIZE-T trial of mitapivat in adults diagnosed with transfusion-dependent alpha- or beta-thalassemia. The company plans to submit an application for regulatory approval of mitapivat as a thalassemia treatment by the end of 2024. 

KOL insights

“There is a tremendous need for oral therapies that can improve how people with thalassemia feel and function and reduce the impact of the disease on their lives. Patients with alpha- or beta-thalassemia, regardless of transfusion status, frequently report negative effects on daily activities and physical functioning. On a number of domains of health-related quality of life, adults with non-transfusion-dependent thalassemia experience even greater symptom burden than their transfusion-dependent counterparts. I am excited about the potential of mitapivat to support quality of life improvements for these individuals.” – MD, Division of Hematology

“The ENERGIZE data presented at this congress show that non-transfusion-dependent alpha- or beta-thalassemia patients treated with mitapivat experienced clinically meaningful improvements in fatigue and walking capacity, as well as improvements in patient-reported outcomes across a range of disease symptoms.” – MD, MSc, FRCPC; Division of Hematology

Conclusion

Currently, there are no approved oral therapies worldwide for non-transfusion-dependent thalassemia, a condition marked by anemia, ineffective erythropoiesis, hemolysis, and iron overload, leading to serious complications, reduced quality of life, and shortened lifespan. Mitapivat potentially represents a novel oral treatment option addressing both the underlying pathophysiology and enhancing health-related quality of life in thalassemia patients. According to data from the ENERGIZE study, mitapivat shows promise as a groundbreaking treatment for non-transfusion-dependent thalassemia. 

According to the data, there was a difference in baseline between mitapivat and placebo of 4.85 vs 1.46 points (p=0.0026) on the FACIT-Fatigue scale. Given that tiredness is among the most incapacitating symptoms experienced by NTD patients, its alleviation is likely to have significant therapeutic implications. The company plans to seek regulatory approval for mitapivat as a thalassemia treatment by late 2024, integrating comprehensive data from pivotal studies. The US launch in thalassemia is expected in 2025. Recently, Agios also reported encouraging results from the Phase III ENERGIZE-T trial in adults with transfusion-dependent alpha- or beta-thalassemia. Improvements in hemolysis, inflammation, and symptom indicators may help distinguish the medication from REBLOZYL (luspatercept) and give hope that comparable outcomes may be observed in sickle cell disease, where quality of life enhancements are crucial.