Durability of Hemoglobin Response and Reduction in Transfusion Burden Is Maintained over Time in Patients with Pyruvate Kinase Deficiency Treated with Mitapivat in a Long-Term Extension Study
Authors: Grace Rachael F. , Glenthoej Andreas , Barcellini Wilma , Verhovsek Madeleine , Rothman Jennifer A. , Morado Marta , Layton D. Mark , Andres Oliver , Galactéros Frédéric , Van Beers Eduard J. , Onodera Koichi , Viprakasit Vip , Chonat Satheesh , Porter John B. , Judge Malia P. , Kosinski Penelope A. , Hawkins Peter , Gheuens Sarah , Xu Emily , McGee Bryan , Beynon Vanessa , Al-Samkari Hanny 
Published: November 2021

Abstract
Background: Pyruvate kinase (PK) deficiency is a rare hereditary anemia caused by mutations in the PKLR gene encoding the red blood cell (RBC) PK enzyme (PKR). Defects in PKR lead to chronic hemolytic anemia, which is associated with serious complications, regardless of transfusion status.
Mitapivat (AG-348) is an investigational, first-in-class, oral, allosteric activator of PKR. Mitapivat demonstrated significant improvements in hemoglobin (Hb), markers of hemolysis and hematopoiesis, and reduction in disease burden (as measured by the PK deficiency diary and PK deficiency impact assessment) in non-regularly transfused patients (pts) (ACTIVATE, NCT03548220) and significant reduction in transfusion burden in regularly transfused pts (ACTIVATE-T, NCT03559699) with PK deficiency. Both studies met their primary endpoints. This analysis reports data from ACTIVATE, ACTIVATE-T, and their long-term extension (LTE) study (NCT03853798).
Methods: The randomized, double-blind, placebo-controlled ACTIVATE study consisted of a 12-week (wk) dose-escalation period (5, 20, 50 mg twice daily [BID]) and a 12-wk fixed-dose period; 80 pts (age ≥ 18 years [yrs]) with a diagnosis of PK deficiency who were not regularly transfused (≤ 4 transfusion episodes in the prior yr; none in the prior 3 months [mos]) were randomized 1:1 to receive mitapivat or placebo. The primary endpoint was Hb response, defined as ≥ 1.5 g/dL increase in Hb from baseline (BL) sustained at ≥ 2 scheduled assessments at Wks 16, 20, or 24 in the fixed-dose period.
The single-arm, open-label ACTIVATE-T study consisted of a 16-wk dose-escalation period (5, 20, 50 mg BID) and a 24-wk fixed-dose period; 27 pts (age ≥ 18 yrs) with a confirmed diagnosis of PK deficiency who were regularly transfused (≥ 6 transfusion episodes in the prior yr) were treated with mitapivat. The primary endpoint was transfusion response (≥ 33% reduction in number of RBC units transfused during the fixed-dose period, compared with the pt's individual historical transfusion burden standardized to 24 wks). A secondary endpoint was achieving transfusion-free status (no transfusions in the fixed-dose period).
Pts who completed the fixed-dose period of ACTIVATE/ACTIVATE-T were eligible to continue in the LTE, where all pts received mitapivat. The ACTIVATE/LTE analysis assessed duration of Hb response in 2 cohorts: 1) pts assigned to mitapivat who achieved a Hb response and continued to the LTE (mitapivat-to-mitapivat arm [M/M]), and 2) pts assigned to placebo who switched to mitapivat in the LTE (placebo-to-mitapivat arm [P/M]) and then met Hb response criteria. The ACTIVATE-T/LTE analysis assessed transfusion response in the LTE, and transfusion-free duration among pts from ACTIVATE-T who achieved transfusion-free status.
Results: In ACTIVATE, 40% of pts treated with mitapivat (N = 40) achieved a Hb response; in the LTE, pts who were randomized to placebo in ACTIVATE showed similar improvements in Hb levels after switching to mitapivat. In both cohorts, these improvements were sustained with continued treatment (Figure 1A). All 16 pts assigned to mitapivat in ACTIVATE who achieved Hb responses continued to the LTE; 15 M/M pts were evaluable for Hb assessment in the LTE. Thirteen of 15 M/M pts (86.7%) maintained ≥ 1.5 g/dL Hb increase from BL up to 19.5 mos at all time points; the other 2 pts maintained ≥1 g/dL Hb increase from BL at all time points (Figure 1B). None of the pts assigned to placebo in ACTIVATE (N = 40) had a Hb response; 17 P/M pts had sufficient time (24 wks of treatment) in the LTE for Hb response assessment. Six of 17 pts (35%) achieved Hb responses in the LTE, and all maintained Hb responses for the duration of follow-up (Figure 1C).
In ACTIVATE-T (N = 27), 37% of pts achieved a transfusion response and 22% of pts achieved transfusion-free status. In the LTE, 9 pts (33.3%) met criteria for a transfusion response. All 6 pts who achieved transfusion-free status in ACTIVATE-T maintained the status in the LTE up to 21.9 mos (Figure 1D). One additional pt, who met the primary endpoint, but was not transfusion free in ACTIVATE-T, did not receive any transfusions in the LTE.
Conclusions: Mitapivat improved Hb and reduced transfusion burden in pts with PK deficiency by targeting the underlying PKR defect. These data show the consistency and long-term durability of response, and support mitapivat's potential to become the first disease-modifying drug therapy approved for PK deficiency.
Figure 1 Figure 1.

Disclosures
Grace: Dova: Membership on an entity's Board of Directors or advisory committees, Research Funding; Principia: Membership on an entity's Board of Directors or advisory committees; Novartis: Research Funding; Agios: Research Funding. Glenthoej: Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees; Calgene: Consultancy, Membership on an entity's Board of Directors or advisory committees; Bluebird Bio: Consultancy, Membership on an entity's Board of Directors or advisory committees; Agios Pharmaceuticals: Consultancy, Membership on an entity's Board of Directors or advisory committees; Alexion: Research Funding; Novo Nordisk: Honoraria. Barcellini: Incyte: Membership on an entity's Board of Directors or advisory committees; Bioverativ: Membership on an entity's Board of Directors or advisory committees; Alexion Pharmaceuticals: Honoraria; Novartis: Honoraria; Agios: Honoraria, Research Funding. Verhovsek: Vertex: Consultancy. Rothman: Pfizer: Consultancy, Honoraria, Research Funding; Agios Pharmaceuticals: Honoraria, Research Funding; Novartis: Honoraria, Research Funding; Bluebird Bio: Research Funding. Morado: Sanofi Genzyme: Honoraria. Layton: Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees; Cerus: Membership on an entity's Board of Directors or advisory committees; Agios Pharmaceuticals: Consultancy, Membership on an entity's Board of Directors or advisory committees. Galactéros: Addmedica: Membership on an entity's Board of Directors or advisory committees. Van Beers: Agios Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Research Funding; RR Mechatronics: Research Funding; Pfizer: Research Funding. Viprakasit: Vifor Pharma: Consultancy, Research Funding; Protagonist Therapeutics: Consultancy, Research Funding; La Jolla Pharmaceuticals: Consultancy, Research Funding; Ionis Pharmaceuticals,: Consultancy, Research Funding; Bristol-Myers Squibb: Consultancy, Honoraria, Research Funding, Speakers Bureau; Agios: Consultancy, Research Funding. Chonat: Alexion: Consultancy, Research Funding; Agios: Consultancy, Research Funding; Novartis: Consultancy, Research Funding; Global Blood Therapeutics: Consultancy, Research Funding; Takeda: Consultancy, Research Funding. Porter: La Jolla Pharmaceuticals: Honoraria; Agios: Consultancy, Honoraria; Silence Therapeutics: Honoraria, Membership on an entity's Board of Directors or advisory committees; bluebird bio, Inc.: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Protagonism: Honoraria; Vifor: Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene (BMS): Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees. Judge: Agios Pharmaceuticals: Current Employment, Current holder of stock options in a privately-held company. Kosinski: Agios Pharmaceuticals: Current Employment, Current equity holder in publicly-traded company. Hawkins: Bristol-Myers Squibb: Current equity holder in publicly-traded company; Agios: Current equity holder in publicly-traded company. Gheuens: Agios Pharmaceuticals: Current Employment, Current equity holder in publicly-traded company. Xu: Agios Pharmaceuticals: Current Employment, Current equity holder in publicly-traded company. McGee: Agios Pharmaceuticals: Current Employment, Current equity holder in publicly-traded company. Beynon: Agios Pharmaceuticals: Current Employment, Current equity holder in publicly-traded company. Al-Samkari: Rigel: Consultancy; Amgen: Research Funding; Dova/Sobi: Consultancy, Research Funding; Novartis: Consultancy; Argenx: Consultancy; Agios: Consultancy, Research Funding; Moderna: Consultancy.