P1735: improvements in patient-reported outcomes in mitapivat-treated patients with pyruvate kinase deficiency: a descriptive analysis from the phase 3 activate trial

Background: Pyruvate kinase (PK) deficiency is a rare, inherited, non-spherocytic hemolytic anemia associated with acute and long-term complications, as well as a spectrum of signs and symptoms including jaundice, fatigue, and dyspnea. PK deficiency has a profound wide-ranging impact on health-related quality of life (HRQoL). Mitapivat (AG-348), a first-in-class, oral, allosteric activator of PK, was shown to improve hemoglobin (Hb), hemolysis, and hematopoiesis in a global, phase 3, randomized, placebo (PBO)-controlled trial evaluating mitapivat efficacy and safety in adults with PK deficiency who were not regularly transfused (ACTIVATE; NCT03548220). Furthermore, significant improvements in patient-reported outcomes (PROs) (measured by disease-specific PRO instruments: the PK deficiency diary [PKDD] and the PK deficiency impact assessment [PKDIA]) were demonstrated in patients (pts) receiving mitapivat compared with PBO. The PKDD is a self-administered, 7-item daily diary to assess the signs and symptoms of PK deficiency (including jaundice, tiredness, and shortness of breath), while the PKDIA is a 12-item weekly measure assessing the impacts of PK deficiency (pts rated the frequency of occurrence or difficulty of various activities). Aims: To describe PKDD and PKDIA outcomes for the subset of pts in the ACTIVATE trial who achieved the primary endpoint of Hb response, defined as a ≥1.5 g/dL increase in Hb from baseline (BL), sustained at ≥2 scheduled assessments at weeks (wks) 16, 20, and 24. Methods: Eighty pts were randomized 1:1 to receive mitapivat (5/20/50 mg twice daily) or PBO for 24 wks in the ACTIVATE trial. Change from BL to wk 24 in PKDD and PKDIA scores were prespecified secondary endpoints. For this post hoc analysis, changes from BL in PKDD weekly mean scores and PKDIA scores measured at scheduled visits (wks 4, 8, 12, 16, 20, and 24) were summarized for Hb responders, the overall mitapivat treatment arm, and PBO, using mean and 95% confidence intervals (CIs). For both the PKDD and the PKDIA, a lower score represents a lower disease burden. Results: In the ACTIVATE trial, 16/40 (40%) pts receiving mitapivat met the primary endpoint of Hb response compared with none for PBO (0/40; 0%). At wk 24, mean (95% CI) change from BL in PKDD weekly mean score was ‒7.12 (‒10.98, ‒3.27) for pts who achieved Hb response, ‒5.43 (‒7.47, ‒3.40) for the overall mitapivat treatment arm, and ‒1.86 (–4.04, 0.32) for the PBO arm (Figure 1a). At wk 24, mean (95% CI) change from BL in PKDIA score was ‒8.07 (‒11.05, ‒5.08) for pts who achieved Hb response, ‒4.82 (‒7.18, ‒2.46) for the overall mitapivat treatment arm, and ‒1.06 (‒3.70, 1.59) for the PBO arm (Figure 1b). Across both PRO instruments, improvements among mitapivat pts who achieved Hb response were sustained over time. Image:Summary/Conclusion: In the ACTIVATE trial, mitapivat-treated pts demonstrated significant improvements in signs, symptoms, and impacts based on PK deficiency-specific PRO instruments, compared with PBO. This analysis further reveals that improvements were greater in the subset of mitapivat-treated pts who achieved the primary endpoint. Together, these data indicate that mitapivat has the potential to improve HRQoL in pts with PK deficiency who are not regularly transfused.