Slide 1: Efficacy and Safety of Mitapivat in Sickle Cell Disease: Results From the Phase 3 RISE UP Trial
Efficacy and Safety of Mitapivat in Sickle Cell Disease: Results From the Global, Randomized, Phase 3 RISE UP Trial Biree Andemariam,1,* Kevin H.M. Kuo,2-4 Farjah Algahtani,5 Salam al Kindi,6 Kenneth I. Ataga,7 Pablo Bartolucci,8 Andrew Campbell,9 Raffaella Colombatti,10 Alexander K. Glaros,11 Kaout
Slide 2: Disclosures
Disclosures • Biree Andemariam has received research funding from Afimmune, Agios Pharmaceuticals, Inc., American Society of Hematology, Connecticut Department of Public Health, US Health Resources and Services Administration, Hemanext, Novartis, Novo Nordisk, and Pfizer; advisory board participatio
Slide 3: Hemolytic anemia is a key driver of complications in sickle cell disease
Hemolytic anemia is a key driver of complications in sickle cell disease • Hemolysis, anemia, and vaso-occlusion contribute to progressive cumulative organ damage in SCD1,2 • Acute anemia and hemolysis in patients with SCD adversely impact quality of life, causing fatigue, shortness of breath, and j
Slide 4: Oral mitapivat enhances RBC metabolism, improving hemolytic anemia
Oral mitapivat enhances RBC metabolism, improving hemolytic anemia and potentially ameliorating the downstream effects of SCD Mitapivat activates pyruvate kinase (PK), including the RBC-specific PKR and the PKM2 isoforms, thereby enhancing RBC metabolism • The overall clinical development program fo
Slide 5: RISE UP is a global, phase 3, double-blind, randomized, placebo-controlled trial
RISE UP is a global, phase 3, double-blind, randomized, placebo-controlled trial of oral mitapivat in patients with SCD Key inclusion criteria • ≥16 years of age at time of informed consent • Confirmed diagnosis of SCD (any subtype) Double-blind period Open-label extension† • Average Hb ≥5.5 g/dL an
Slide 6: RISE UP has two primary endpoints; achieving either was a positive outcome
Phase 3 RISE UP has two primary endpoints; achieving either was a positive outcome of the study Two primary endpoints Hierarchy of key secondary endpoints Hb response*,† Annualized α1 = 0.02 Average change in Average change in Average change in Average change in frequency of PROMIS Fatigue percentag
Slide 7: Patient disposition
Patient disposition 294 patients were assessed for eligibility 87 patients did not meet the eligibility criteria 207 patients were randomly assigned in a 2:1 ratio 138 assigned and 69 assigned and received mitapivat 100 mg BID received placebo 13% (18 patients) discontinued 5 patients due to withdra
Slide 8: Patient disposition
Patient disposition 294 patients were assessed for eligibility 87 patients did not meet theeligibility criteria 207 patients were randomly assigned in a 2:1 ratio 138 assigned and 69 assigned and received mitapivat 100 mg BID received placebo Of the 176 patients who completed 13% (18 patients) disco
Slide 9: Baseline characteristics were balanced between arms
Baseline characteristics were balanced between arms Mitapivat 100 mg BID (N=138) Placebo (N=69) Age, median (Q1, Q3), years 25.0 (20.0; 34.0) 27.0 (22.0; 37.0) Sex, female, n (%) 76 (55.1) 43 (62.3) Race, n (%)* Black or African American 103 (74.6) 53 (76.8) White 20 (14.5) 8 (11.6) Asian 1 (0.7) 1
Slide 10: Mitapivat met the primary endpoint of Hb response compared with placebo
Mitapivat met the primary endpoint of Hb response compared with placebo Difference in response rates, mitapivat vs placebo, % (95% CI) 37.7 (28.6; 46.8) Two-sided p<0.0001 Response defined as an increase of ≥1.0 g/dL in average Hb concentration from Week 24 through Week 52 *Includes 13 patients with
Slide 11: Mitapivat met the primary endpoint of Hb response compared with placebo
Mitapivat met the primary endpoint of Hb response compared with placebo Difference in response rates, mitapivat vs placebo, % (95% CI) Among responders in the mitapivat arm, 37.7 (28.6; 46.8) mean (SD) change from baseline in average Hb Two-sided p<0.0001 concentration from Week 24 to Week 52 was 1.
Slide 12: Hb response was not driven by any pre-specified subgroup
Hb response was not driven by any pre-specified subgroup Hemoglobin response rate, % (n/N) Mitapivat Characteristic Subgroup Placebo 100 mg BID Difference in hemoglobin response rate (95% CI)† Difference (95% CI) All patients (stratified)* 2.9 (2/69) 40.6 (56/138) 37.7 (28.6; 46.8) Yes 2.0 (1/51) 40
Slide 13: Significant improvements in anemia and hemolysis were rapid and sustained over time
Significant improvements in anemia and hemolysis were rapid and sustained over time in the mitapivat arm Key secondary endpoints Hemoglobin (g/dL) Indirect bilirubin (μmol/L) Mitapivat Placebo LSM difference Mitapivat Placebo LSM difference 100 mg BID 100 mg BID N=138 N=69 2-sided p-value N=138 N=69
Slide 14: Improvements in hemolysis were accompanied by favorable clinical trends
Improvements in hemolysis were accompanied by favorable clinical trends Rate reduction or Mitapivat 100 mg BID Placebo Two-sided LSM difference (95% CI), N=138 N=69 p-value mitapivat vs placebo Primary endpoint SCPCs, annualized rate (95% CI) 2.62 (2.29; 3.01) 3.05 (2.57; 3.64) 14% (−4.1%; 29.2%) 0.
Slide 15: Clinically meaningful reduction in transfusion burden compared with placebo
Clinically meaningful reduction in transfusion burden was observed for mitapivat compared with placebo Mitapivat 100 mg BID Placebo N=138 N=69 Patients transfused, n (%) 33 (23.9) 28 (40.6) Relative reduction, mitapivat vs placebo 41.1% Total number of RBC units transfused 97 110 Average RBC units t
Slide 16: Improvements in SCPC and healthcare utilization in Hb responders vs non-responders
Improvements in SCPC and healthcare utilization were more pronounced and clinically meaningful in Hb responders vs non-responders in the mitapivat arm 26%* 53%† 37%§ 34%‡ All graphs depict the LSM (+/-95% CI) for the average change from baseline from Week 24 through Week 52. Percentages reported rep
Slide 17: Hb responders experienced greater improvements in fatigue vs non-responders
Hb responders in the mitapivat arm experienced greater improvements in fatigue vs non-responders PROMIS Fatigue 13a Short Form T-scores 0 LSM (±95% Cl) change from baseline –1 –2 –3 –4 –5 -2.55 –6 –7 –8 -5.19 –9 Hemoglobin Hemoglobin non-responders responders Reductions in scores represent improveme
Slide 18: Reduction in fatigue among Hb responders exceeded the clinically meaningful threshold
The magnitude of reduction in fatigue among Hb responders exceeded the clinically meaningful change threshold PROMIS Fatigue 13a Short Form T-scores 0 LSM (±95% Cl) change from baseline –1 –2 –3 –4 Meaningful within-person change threshold: -4.1 points –5 -2.55 –6 –7 –8 -5.19 –9 Hemoglobin Hemoglobi
Slide 19: Hb responders experienced consistent improvements in how they felt and functioned
Hb responders experienced consistent improvements in how they felt and functioned compared to Hb non-responders Change from baseline (95% CI) LSM difference of Hb responder Hb non-responder Hb responders vs n=56 n=82 non-responders −1.63 −0.59 −1.04 (−1.66; −0.42) PROMIS Pain Intensity 1a* Favors Hb
Slide 20: Mitapivat was well-tolerated, with an acceptable safety profile in patients with SCD
Mitapivat was well-tolerated, with an acceptable safety profile in patients with SCD Mitapivat 100 mg BID Placebo • There was a similar percentage of patients with Patients, n (%) N=138 N=69 any reported TEAEs, including grade ≥3 events, Any TEAEs 134 (97.1) 68 (98.6) in the mitapivat and placebo ar
Slide 21: Most commonly reported TEAEs
Most commonly reported TEAEs Mitapivat 100 mg BID Placebo Most common TEAEs, n (%)* N=138 N=69 Arthralgia 41 (29.7) 13 (18.8) Pain in extremity 38 (27.5) 16 (23.2) Headache 34 (24.6) 14 (20.3) Back pain 30 (21.7) 18 (26.1) Fatigue 24 (17.4) 9 (13.0) Malaria 23 (16.7) 9 (13.0) Upper respiratory tract
Slide 22: Conclusions: Phase 3 RISE UP
Conclusions: Phase 3 RISE UP • Mitapivat demonstrated a strong anti-hemolytic effect, which resulted in clear clinical benefits: § Significantly higher proportion of patients with a rapid and durable Hb response compared with placebo § Reduction in transfusion burden compared with placebo § For Hb r
Slide 23: Conclusions: Mitapivat in SCD
Conclusions: Mitapivat in SCD This pivotal study is the first to validate pyruvate kinase activation as a new treatment paradigm in sickle cell disease Mitapivat, through its oral administration and novel mechanism for improving hemolytic anemia, can be an effective and convenient disease-modifying
Slide 24: Acknowledgments
Acknowledgments • We thank the patients, their families, and all investigators involved in the RISE UP study Supplemental data are available via the QR code • This study was funded by Agios Pharmaceuticals, Inc. • Medical writing was provided by ApotheCom, San Francisco, CA, USA, and was funded by A