ALBERT

Description: Background: Pyruvate kinase (PK) deficiency is a congenital hemolytic anemia caused by mutations in the PKLR gene, leading to a deficiency of the glycolytic enzyme red cell PK (PK-R). Current treatments for PK deficiency are supportive only. Mitapivat (AG-348) is an oral, small-molecule, allosteric PK-R activator in clinical trials for PK deficiency. We previously described results from DRIVE PK, a phase 2, randomized, open-label, dose-ranging study in adults with PK deficiency (N=52) treated with mitapivat for a median of 6 months. Aim: To report long-term safety and efficacy of mitapivat in patients who continue treatment in the ongoing Extension period of the DRIVE PK study (ClinicalTrials.gov NCT02476916). Methods: Patients were eligible to participate if ≥18 years of age with a confirmed diagnosis of PK deficiency (enzyme and molecular testing); baseline hemoglobin (Hb) levels ≤12.0 g/dL (males) or ≤11.0 g/dL (females); and if they had not received more than 3 units of red blood cells in the prior 12 months, with no transfusions in the prior 4 months. Patients were initially randomized 1:1 to receive mitapivat 50 mg twice daily (BID) or 300 mg BID for a 6-month Core period. Dose adjustment was allowed during the Core period based on safety and efficacy. Patients experiencing clinical benefit without concerning safety issues related to mitapivat (investigator discretion) could opt to enter the Extension period, with follow-up visits every 3 months. Safety (adverse events [AEs]) and efficacy (hematologic parameters including Hb) were assessed. Protocol amendments during the Extension period required that (1) patients who did not have an increase from baseline Hb of ≥1.0 g/dL for ≥3 of the prior 4 measurements withdraw from the study, and (2) patients treated with mitapivat doses 〉25 mg BID undergo a dose taper and continue on the dose that maintained their Hb level no lower than 1.0 g/dL below their pre-taper Hb level. Results: Fifty-two patients enrolled in this study and were treated in the 24-week Core period; 43 (83%) patients completed the Core period and 36 (69%) entered the Extension period. Eighteen patients discontinued from the Extension period: investigator decision (n=8), AEs (n=1), consent withdrawal (n=1), noncompliance (n=1), or other (n=7). Thus, 18 patients, all of whom received ≥29 months of treatment with mitapivat (median 35.6, range 28.7-41.9) have continued treatment. Ten of these 18 patients were male, 11 had a prior splenectomy, and 5 had a history of iron chelation. Median age was 33.5 (range 19-61) years; mean baseline Hb was 9.7 (range 7.9-12.0) g/dL. All patients had ≥1 missense PKLR mutation. The doses (post-taper) at which treatment was continued were (BID): ≤25 mg (n=12), 50 mg (n=5), and 200 mg (n=1). Improvements in Hb levels and markers of hemolysis (reticulocytes, indirect bilirubin, haptoglobin) were sustained (Figure). Among the 18 patients, headache was the most commonly reported AE during both the Extension (n=7, 38.9%) and Core (n=10, 55.6%) periods. Reports of insomnia and fatigue during the Extension period (n=5, 27.8% each) were the same as or similar to those during the Core period. There were fewer reports of nausea (2 vs 6) and hot flush (0 vs 5) in the Extension period. Nasopharyngitis was reported in 5 patients in the Extension period vs 1 patient in the Core period. These data are consistent with the AE profile for the 52 patients treated overall in the Core period, in that headache (44%), insomnia (40%), and nausea (38%) were the most commonly reported AEs and were transient (generally resolved within 7 days without intervention). Conclusion: Chronic daily dosing with mitapivat for a median of 3 years was well tolerated, with no new safety signals reported. Increased Hb levels and improvements in hemolysis markers were sustained at the optimized individual doses. These long-term data support the potential of mitapivat as the first disease-altering therapy for PK deficiency. Two phase 3 trials are underway to further study the effect of mitapivat in patients with PK deficiency. Disclosures Grace: Novartis: Research Funding; Agios Pharmaceuticals, Inc: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding. Layton:Novartis: Membership on an entity's Board of Directors or advisory committees; Cerus Corporation: Membership on an entity's Board of Directors or advisory committees; Agios: Membership on an entity's Board of Directors or advisory committees. Galactéros:Addmedica: Membership on an entity's Board of Directors or advisory committees. Barcellini:Novartis: Research Funding, Speakers Bureau; Alexion: Consultancy, Research Funding, Speakers Bureau; Apellis: Consultancy; Incyte: Consultancy, Other: Advisory board; Agios: Consultancy, Other: Advisory board; Bioverativ: Consultancy, Other: Advisory board. van Beers:Agios Pharmaceuticals, Inc.: Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Consultancy, Research Funding; Pfizer: Research Funding; RR Mechatronics: Research Funding. Ravindranath:Agios Pharmaceuticals, Inc.: Other: I am site PI on several Agios-sponsored studies, Research Funding. Kuo:Agios: Consultancy; Alexion: Consultancy, Honoraria; Apellis: Consultancy; Bioverativ: Other: Data Safety Monitoring Board; Bluebird Bio: Consultancy; Celgene: Consultancy; Novartis: Consultancy, Honoraria; Pfizer: Consultancy. Sheth:Apopharma: Other: Clinical trial DSMB; CRSPR/Vertex: Other: Clinical Trial Steering committee; Celgene: Consultancy. Kwiatkowski:bluebird bio, Inc.: Consultancy, Research Funding; Apopharma: Research Funding; Novartis: Research Funding; Terumo: Research Funding; Celgene: Consultancy; Imara: Consultancy; Agios: Consultancy. Hua:Agios Pharmaceuticals, Inc.: Employment, Equity Ownership. Hawkins:Bristol Myers Squibb: Equity Ownership; Infinity Pharma: Equity Ownership; Agios: Employment, Equity Ownership; Jazz Pharmaceuticals: Equity Ownership. Mix:Agios: Employment, Equity Ownership. Glader:Agios Pharmaceuticals, Inc: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding.

Description: Background: Eculizumab was demonstrated to effectively treat and prevent thrombotic microangiopathy (TMA) and to improve renal function and hematologic parameters for up to 2 years in4 previous prospective clinical trials and in 1 retrospective study of patients with atypical hemolytic uremic syndrome (aHUS). Patients in these studies enrolled in a long-term follow-up study, in which rates of TMA were evaluated during eculizumab treatment and during discontinuation from eculizumab. Methods: Data were gathered from an ongoing, observational, multicenter study of aHUS patients treated with eculizumab in 5 prior clinical studies. The primary endpoint was TMA event rate post-parent study during on-treatment (ON; among patients receiving eculizumab) and off-treatment (OFF; among patients who discontinued eculizumab) periods. Results: As of March 28, 2015, 87 patients, including 35 children

Description: Background: Pyruvate kinase (PK) deficiency is an under-recognized hereditary disease that causes lifelong hemolytic anemia. Mutations in the PKLR gene lead to reduced red cell PK (PK-R) enzyme activity, resulting in defective glycolysis and decreased lifespan of red blood cells. Mitapivat (AG-348) is a novel, first-in-class, oral, small-molecule allosteric activator of PK-R under clinical testing as the first targeted, disease-altering therapy for PK deficiency. The DRIVE PK study (NCT02476916; a phase 2, open-label, dose-ranging trial in adults with PK deficiency who are not regularly transfused) demonstrated that twice-daily (BID) dosing with mitapivat for 〉6 months was well tolerated and induced rapid, substantial, and durable responses (Grace et al. ASH 2017). Of 52 enrolled subjects, 26 (50%) had a maximum hemoglobin (Hb) increase of 〉1 g/dL in the 6-month treatment period. Among these 26 subjects, the mean maximum Hb increase was 3.4 g/dL, and 25 (96%) had ≥1 missense PKLR mutation. Based on these findings, mitapivat has entered phase 3 development in PK deficiency. The design of the ongoing phase 3 ACTIVATE study and its extension study are reported here, with an update on country/site activation. Methods: ACTIVATE is a phase 3, multicenter, randomized, double-blind, placebo-controlled study (NCT03548220) evaluating the efficacy and safety of mitapivat. Adults with PK deficiency who are not regularly transfused (≤4 transfusion episodes in the previous year and no transfusions in the prior 3 months) will be randomized in a 1:1 ratio to mitapivat (administered orally, BID) or matched placebo. Additional criteria include baseline Hb ≤10.0 g/dL and adequate organ function. Subjects who are homozygous for the R479H mutation or have 2 non-missense mutations (without the presence of another missense mutation) in PKLR will be excluded. The study consists of a screening period of up to 42 days, a 12-week dose optimization period, and a 12-week fixed-dose period (Figure). During the dose optimization period, mitapivat or matched placebo are titrated up to each subject's individually optimized dose, with an initial dose of 5 mg BID for all subjects and potentially 2 sequential dose increases (from 5 to 20 mg BID and from 20 to 50 mg BID), depending on safety and Hb change. The primary endpoint is the Hb response, defined as the proportion of subjects who achieve an increase of ≥1.5 g/dL in Hb sustained over at least 2 of the last 3 visits in the fixed-dose period. The average change in Hb during the fixed-dose period is considered a key secondary endpoint to further evaluate the magnitude of the treatment effect. Other secondary efficacy endpoints, such as markers of hemolysis and hematopoietic activity, will be evaluated to support the efficacy evaluation and confirm the mechanism of action, and safety is included as a secondary objective and endpoint. Two questionnaires, one specifically designed to measure the signs and symptoms of PK deficiency and the other designed to evaluate their impact on patients' lives, are also included for their validation and to further evaluate the efficacy of the treatment. All subjects who complete the study have the opportunity to enroll in an open-label extension study (NCT03853798) in which all participants will receive mitapivat for up to 192 weeks. An independent data monitoring committee will review the study data periodically and provide safety oversight. The ACTIVATE study is currently ongoing. Disclosures van Beers: Novartis: Consultancy, Research Funding; Pfizer: Research Funding; RR Mechatronics: Research Funding; Agios Pharmaceuticals, Inc.: Membership on an entity's Board of Directors or advisory committees, Research Funding. Judge:Agios: Employment, Equity Ownership. Hua:Agios Pharmaceuticals, Inc.: Employment, Equity Ownership. Mix:Agios: Employment, Equity Ownership.

Description: Background: Pyruvate kinase (PK) deficiency is an under-recognized hereditary disease that causes lifelong hemolytic anemia. Mutations in the PKLR gene lead to reduced red cell PK (PK-R) enzyme activity, resulting in defective glycolysis and decreased lifespan of red blood cells. Mitapivat (AG-348) is a novel, first-in-class, oral, small-molecule allosteric activator of PK-R under clinical testing as the first targeted, disease-altering therapy for PK deficiency. In the DRIVE PK study (NCT02476916; a phase 2, open-label, dose-ranging trial in adults with PK deficiency who are not regularly transfused), twice-daily (BID) dosing with mitapivat for 〉6 months was well tolerated and induced rapid, durable responses (Grace et al. ASH 2017). As of July 14, 2017, 26 (50%) of 52 enrolled subjects had a maximum hemoglobin (Hb) increase of 〉1 g/dL. Among these 26 subjects, the mean maximum Hb increase was 3.4 g/dL, and 25 (96%) had ≥1 missense PKLR mutation. Based on these findings, mitapivat has entered phase 3 clinical development. The design of the ongoing phase 3 ACTIVATE-T study and its extension study are reported here, with an update on country/site activation and key early learnings on trial logistics in PK deficiency. Methods: ACTIVATE-T is a global, multicenter, open-label study (NCT03559699) to evaluate the efficacy and safety of mitapivat in regularly transfused adults with PK deficiency. Regularly transfused is defined as ≥6 transfusion episodes in the previous year. Subjects who are homozygous for the R479H mutation or have 2 non-missense mutations (without the presence of another missense mutation) in PKLR will be excluded, as will subjects with an average transfusion frequency of more than once every 3 weeks in the previous year. The study comprises an 8-week screening period, during which each subject's complete transfusion history from the prior 52 weeks is documented, followed by a 16-week dose optimization period and a 24-week fixed-dose period (Figure). During the dose optimization period, each subject will undergo individualized mitapivat dose optimization. All subjects will start on a dose of 5 mg BID, which may be increased twice over the course of 16 weeks (from 5 to 20 mg BID and from 20 to 50 mg BID). In the fixed-dose period, each subject will receive mitapivat at their optimized dose for 24 weeks. During the study, subjects will be transfused when their Hb reaches or falls below their individual transfusion trigger calculated from their transfusion history. The primary endpoint is the proportion of subjects who achieve a reduction in transfusion burden, defined as a reduction of ≥33% in the number of red blood cell units transfused during the 24 weeks of the fixed-dose period compared with the historical transfusion burden standardized to 24 weeks. Secondary endpoints include safety. All subjects who complete the study will have the opportunity to enroll in an open-label extension study (NCT03853798) in which all participants will receive mitapivat for up to 192 weeks. The ACTIVATE-T trial is enrolling globally. Disclosures Lynch: Agios: Employment, Equity Ownership. Hua:Agios Pharmaceuticals, Inc.: Employment, Equity Ownership. Mix:Agios: Employment, Equity Ownership. Porter:Bluebird bio: Consultancy, Honoraria; Silence therapeutics: Honoraria; Vifor: Honoraria; La Jolla: Honoraria; Protagonism: Honoraria; Celgene: Consultancy, Honoraria; Agios: Consultancy, Honoraria.