Long-Term Improvements in Patient-Reported Outcomes in Patients with Pyruvate Kinase Deficiency Treated with Mitapivat

Background: Pyruvate kinase (PK) deficiency is a rare, hereditary hemolytic anemia caused by a single gene defect encoding the red blood cell (RBC)-specific form of PK. This condition is associated with acute and long-term complications, as well as a spectrum of signs and symptoms including jaundice, fatigue, and dyspnea, that have a profound, wide-ranging impact on health-related quality of life (HRQoL). Patients (pts) report physical limitations, negatively impacted social functioning, reduced self-esteem, and concerns for the future. Mitapivat, a first-in-class, oral, allosteric activator of PK, has demonstrated improvement in hemoglobin, hemolysis, and transfusion burden in pts with PK deficiency, and is approved by the US Food and Drug Administration for the treatment of hemolytic anemia in adults with PK deficiency. In addition, 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 observed in two global, phase 3 clinicals trials among adults with PK deficiency treated with mitapivat who were not regularly (ACTIVATE; NCT03548220) or regularly transfused (ACTIVATE-T; NCT03559699). Here, we describe PKDD and PKDIA outcomes up to Week (Wk) 84 of the long-term extension (LTE) study (NCT03853798) of mitapivat in pts with PK deficiency previously enrolled in ACTIVATE and ACTIVATE-T.

Methods: In the placebo (PBO)-controlled ACTIVATE trial, pts were randomized 1:1 to receive mitapivat (5/20/50 mg twice daily) or PBO for 24 wks. In the open-label, single-arm ACTIVATE-T trial, pts were treated with mitapivat for 40 wks. Pts who completed either trial were eligible to continue in the LTE, where all pts received mitapivat. Pts from ACTIVATE were categorized into either the mitapivat-to-mitapivat arm (M/M) or the PBO-to-mitapivat arm (P/M). Pts from ACTIVATE-T continued to receive mitapivat (M). Two PK deficiency-specific PRO instruments were used: the PKDD is a 7-item measure of the core signs and symptoms of PK deficiency, and the PKDIA is a 14-item measure of the impacts of PK deficiency on pts' HRQoL. In the ACTIVATE/LTE and ACTIVATE-T/LTE analyses, changes from baseline (BL; defined as the last complete assessment before start of study treatment in ACTIVATE/ACTIVATE-T) in PKDD and PKDIA mean scores were assessed at scheduled visits up to Wk 84 of the LTE for each of the 3 treatment arms. For both PRO instruments, a lower score represents a lower disease burden, and the minimal clinically important change is defined as a reduction of 4.2 and 5.5 in PKDD and PKDIA scores, respectively. Changes in PKDD and PKDIA scores were summarized descriptively using mean and SD.

Results: In total, 80 pts were included in the ACTIVATE/LTE analysis (M/M=40; P/M=40) and 27 pts were included in the ACTIVATE-T/LTE analysis. At Wk 84 of the LTE study (ie, Wk 108 for ACTIVATE pts; Wk 124 for ACTIVATE-T pts), mean (SD) change from BL in PKDD score was ‒7.19 (6.740) for M/M pts, ‒4.58 (5.758) for P/M pts, and ‒3.94 (14.087) for M pts; mean (SD) change from BL in PKDIA score was ‒6.3 (7.12) for M/M pts, ‒6.3 (9.09) for P/M pts, and ‒11.5 (11.53) for M pts. Notably, P/M pts experienced improvements in PKDD and PKDIA mean scores after starting mitapivat in the LTE that were consistent with initial improvements seen in the mitapivat-treated group in the ACTIVATE trial. Across both PRO instruments, improvements among mitapivat-treated pts were sustained over time in the LTE (Figures 1A and 1B).

Conclusions: Treatment with mitapivat was associated with long-term, durable, and clinically meaningful improvements in signs, symptoms, and functional impacts based on disease-specific PRO instruments, irrespective of transfusion status. These results suggest that by improving HRQoL, treatment with mitapivat may provide meaningful pt-centric benefits.