Study design of the phase 3 portion of RISE UP: A phase 2/3, randomized, double blind, placebo controlled study of mitapivat in patients with sickle cell disease

Study design of the phase 3 portion of RISE UP: A phase 2/3, randomized, double-blind,placebo-controlled study of mitapivat in patients with sickle cell disease

P2193

Biree Andemariam, MD1, Wally R Smith, MD2, Eduard J van Beers, MD3, Swee Lay Thein, MD4, Kevin HM Kuo, MD, MSc, FRCPC5, Miguel R Abboud, MD6, Obiageli E Nnodu, BMBCH, FWACP (LabMed), FNAMed7, Kenneth I Ataga, MD8, Andrew Campbell, MD9, Deepika S Darbari, MD10, Salam al Kindi, FRCP11, Ibrahim M Idris, MBBS, MPH12, Abdulafeez Oluyadi, PharmD13, James Xiao, PhDa,13, Susan Morris, PhD13, Sarah Gheuens, MD, PhD, MMSc13, Kareem Osman, MD13, Ahmar U Zaidi, MD13, Raffaella Colombatti, MD, PhD14

1New England Sickle Cell Institute, UConn Health, Farmington, CT, USA; 2Virginia Commonwealth University, Richmond, VA, USA; 3Center for Benign Hematology, Thrombosis and Hemostasis - Van Creveldkliniek, University Medical Center Utrecht, Utrecht University, Utrecht, The Netherlands; 4Sickle Cell Branch, National Heart, Lung & Blood Institute, NIH, Bethesda, MD, USA; 5Division of Hematology, University of Toronto, Toronto, ON, Canada; 6Department of Pediatrics and Adolescent Medicine, American University of Beirut Medical Center, Beirut, Lebanon; 7Department of Hematology and Blood Transfusion, Centre of Excellence for Sickle Cell Disease Research and Training, College of Health Sciences, University of Abuja, Abuja, Nigeria; 8Center for Sickle Cell Disease, University of Tennessee Health Science Center, Memphis, TN, USA; 9Division of Hematology, Children's National Hospital, Washington, DC, USA; 10Children's National Hospital, Washington, DC, USA; 11Department of Hematology, Sultan Qaboos University, Muscat, Oman; 12Department of Haematology, Aminu Kano Teaching Hospital/Bayero University, Kano, Nigeria; 13Agios Pharmaceuticals, Inc., Cambridge, MA, USA; 14Pediatric Hematology Oncology Unit, Azienda Ospedale-Università di Padova, Padova, Italy.

aEmployee of Agios Pharmaceuticals, Inc. at time of research

BACKGROUND

Introduction to sickle cell disease (SCD)

• SCD is a serious, inherited hemoglobin (Hb) disorder caused by a mutation in the ß-globin gene1,2
• Most patients with SCD are homozygous for sickle cell Hb (HbSS), but some individuals may have coinherited hemoglobin S (HbS) with another ß-globin chain variant, for example, HbS plus a hemoglobin C (HbC; HbSC)
  or ß-thalassemia gene variant1,3
• A recent analysis estimated that between 2000 and 2021, worldwide prevalence of SCD rose by 41.4% from 5.5 million to 7.7 million4
• Fatigue and pain from SCD have a high impact on health-related quality of life, limiting daily function, schooling, and employment5

Pathophysiology of SCD and role of pyruvate kinase (PK)

• Red blood cells (RBCs) in SCD are distorted and stiff, with increased adhesiveness, which causes impeded blood flow, vaso-occlusion, and pain6,7
• Distorted (sickled) RBCs also have shortened lifespans, resulting in hemolytic anemia and fatigue2,7,8
• Both vaso-occlusion and hemolysis contributes to vasculopathy and endothelial dysfunction2,9
• PK is a key enzyme in RBC metabolism and ATP production; its activity and stability are decreased in SCD10 (Figure 1)
• The glycolytic intermediate 2,3-diphosphoglycerate (DPG) is increased, preferentially binding to and stabilizing deoxy-HbS10-13; ATP (a product of glycolysis) is decreased, leading to RBC dehydration12,13
• • Both factors promote HbS polymerization11,13
• In SCD, the activity and stability of PK and the ratio of ATP:2,3-DPG are decreased10

Figure 1. PK activation in SCD may improve anemia and reduce sickling14

Glucose

GLYCOLYSIS

Mitapivat as a potential therapy for SCD

• Mitapivat, a first-in-class, oral, small-molecule allosteric activator of PK, including RBC-specific PK (PKR) and PK muscle isoenzyme 2 (PKM2) isoforms, is under investigation for the treatment of SCD15-17 (Figure 1)
• In the phase 2, dose-finding portion of RISE UP (NCT05031780):
• • Treatment with mitapivat demonstrated statistically significant and clinically meaningful improvements in Hb response compared with placebo17
  • Reductions in annualized rates of sickle cell pain crises
    (SCPCs; defined by an acute pain episode, acute chest syndrome, priapism, hepatic sequestration, or splenic sequestration)
    and improvements in markers of hemolysis and erythropoiesis were observed17
• Mitapivat was well tolerated, with a safety profile consistent with previous studies17
• Mitapivat 100 mg twice daily (BID) was selected as the dose for the phase 3 portion of the phase 2/3 RISE UP trial, conducted in patients with SCD
• The primary and key secondary objectives and endpoints, and the safety objectives for the phase 3 portion of the RISE UP trial are displayed in Tables 1-3

OBJECTIVE

•To report the design of the phase 3 portion of RISE UP, a global, phase 2/3, double-blind, randomized, placebo-controlled trial evaluating the efficacy and safety of mitapivat in patients with SCD

METHODS

Study design

• In the double-blind, phase 3 portion of the RISE UP study, 198

patients (who did not participate in the phase 2 dose-finding

portion) are being randomized 2:1 to receive mitapivat 100 mg

BID or matched placebo for 52 weeks (Figure 2)

• Randomization will be stratified by the number of SCPCs in

the prior year (<5, ≥5) and concomitant hydroxyurea use

• Patients who complete the double-blind period will be eligible

to receive mitapivat for an additional 216 weeks in an

Key inclusion criteria for phase 2/3 trial

• Aged ≥16 years (≥18 years in France and Germany)
• Confirmed SCD diagnosis (HbSS, HbSC, HbS/ß0- thalassemia, HbS/ß+-thalassemia, or other sickle cell syndrome variants)
• 2-10SCPCs in the 12 months prior to providing informed consent (defined as acute pain needing medical contact and treatment, acute chest syndrome, priapism needing medical contact, or hepatic or splenic sequestration)
• Hb level of 5.5-10.5 g/dL (based on an average of ≥2 Hb concentration measurements separated by ≥7 days and collected during the screening period)
• Patients receiving concomitant hydroxyurea can participate; however, the dose must be stable for ≥90 days prior to randomization
• Women of childbearing potential must agree to be abstinent or use 2 forms of contraception

Key exclusion criteria for phase 2/3 trial

• Pregnant, breastfeeding, or parturient
• Individuals receiving scheduled RBC transfusions (episodic transfusions in response to worsened anemia or vaso-occlusive crises are permitted)
• Hospitalized for an SCPC or other vaso-occlusive event within 14 days prior to providing informed assent/consent or during the screening period
• Individuals receiving treatment with disease-modifying SCD therapies other than hydroxyurea, or hematopoietic stimulating agents (last dose of such therapies must have been administered ≥90 days prior to randomization)
• Severe kidney disease or hepatobiliary disorders

Table 1. RISE UP primary objectives and endpoints

Primary objectives	Primary endpoints
To determine the effect of mitapivat vs placebo on:	Measured by:
Anemia	Hb response; defined as a ≥1.0 g/dL increase in average Hb concentration
from Week 24 through Week 52 compared with baseline
SCPCs	Annualized rate of SCPCs

If either of the primary endpoints is met, key secondary efficacy endpoints

will be tested at the time of the primary analysis

Hb, hemoglobin; SCPC, sickle cell pain crisis

RESULTS

Enrollment status

• Patients are currently being enrolled into the phase 3 portion of the RISE UP trial
• Recruitment is anticipated to take place across approximately 100 sites globally (Figure 3)

Figure 3. SCD phase 2/3 study geographic distributiona

Canada	Netherlands
	Germany
	Belgium
	Italy
	UK
	France	Lebanon Turkey
USA		Saudi Arabia
Israel
		Oman
	Ghana	Kenya
Brazil	Nigeria

aCountries with sites approved or under consideration SCD, sickle cell disease

CONCLUSIONS

•The phase 3 portion of RISE UP will assess the efficacy and safety of mitapivat compared with placebo in patients with SCD, at the dose identified in the phase 2 portion of the study (100 mg BID)

•Mitapivat, a small-molecule allosteric activator of PK, has the potential to be the first novel oral therapy approved to address both hemolytic anemia and SCPCs in patients with SCD

Additional information on the RISE UP study can be

found at ClinicalTrials.gov (NCT05031780)

and from [e-mail]

FBP

Decreasing 2,3-DPG reduces HbS

open-label extension

Table 2. Key secondary objectives and endpoints

polymerization by increasing Hb

Key secondary objectives

Key secondary endpoints

Acknowledgments: We would like to thank all the patients and study investigators for taking

1,3-DPG

3-PG

PEP

PK

2,3-DPG

ADP

oxygenation and may inhibit the sickling process

Figure 2. RISE UP phase 3 study design

Phase 3 primary endpoints: Hb response, defined as a ≥1.0 g/dL increase in average Hb concentration

from Week 24 through Week 52 compared with baseline, and annualized rate of SCPCs

3	period days)	(2:1)	Mitapivat

-up last dose)

study

To determine the effect of mitapivat vs placebo on:

Anemia

Markers of hemolysis

Markers of erythropoiesis

Patient-reported fatigue

Measured by:

Average change from baseline Hb concentration from Week 24 through Week 52

Average change from baseline in indirect bilirubin from Week 24 through Week 52

Average change from baseline in percent reticulocytes from Week 24 through Week 52

Average change from baseline in Patient-Reported Outcomes Measurement Information System® Fatigue 13a Short Form scores from Week 24 through Week 52

part in this trial, and for contributing to the design of this study. Medical writing assistance was provided by Hennah Patel, MPharm, RPh, of Adelphi Group, Macclesfield, UK, funded by Agios Pharmaceuticals, Inc.

Disclosures: This study was funded by Agios Pharmaceuticals, Inc.

BA: Afimmune, American Society of Hematology, Connecticut Department of Public Health, Forma Therapeutics, Hemanext, HRSA, Novartis, PCORI, Pfizer - IPI/research funding; Accordant, Afimmune, Agios, bluebird bio, Forma Therapeutics, Genentech, GlaxoSmithKline, Global Blood Therapeutics, Hemanext, Novartis, Novo Nordisk, Pfizer, Protagonist Therapeutics, Sanofi Genzyme, Vertex - advisory board participation/consultancy. WRS: Agios - consultancy and research funding. EJvB: Agios - advisory board member; Agios, Novartis, Pfizer, RR Mechatronics - research funding. SLT: Nothing to declare. KHMK: Agios, Alexion, Biossil, Bristol-Myers Squibb, Novo Nordisk, Pfizer, Vertex - consultancy; Alexion,

Mitapivat

ATP		Increasing ATP enhances
		RBC energy metabolism and

	Phase				Randomization N=198
		Screening (up to 28			(100 mg BID)
					Mitapivat
					(100 mg BID)
				Matched placebo

Safety follow days after

End of

Additional clinical efficacy measures related to SCPCs

Hb, hemoglobin; SCPC, sickle cell pain crisis

Annualized frequency of hospitalizations for SCPCs

Bristol-Myers Squibb, Vertex - honoraria; Agios, Sangamo - membership on an entity's Board of Directors or advisory committees; Agios, Pfizer - research funding. MRA: Agios - advisory board member; Novartis - research funding; Vertex - data monitoring committee; Pfizer - research funding; Roche - travel grant; Novo Nordisk - research funding. OEN: Agios

may improve membrane integrity

(28

Table 3. RISE UP safety objective and endpoint

- advisory board member. KIA: Novartis, Novo Nordisk - research funding; Agios, Biomarin,

Fulcrum Therapeutics, Hillhurst Biopharmaceutics, Novartis, Novo Nordisk, Pfizer, Sanofi

References and

Pyruvate

ADP, adenosine diphosphate; DPG, diphosphoglycerate; FBP, fructose bisphosphate; Hb, hemoglobin; HbS, hemoglobin S; PEP, phosphoenolpyruvate; PG, phosphoglycerate; PK, pyruvate kinase; RBC, red blood cell; SCD, sickle cell disease

Double-blind period: 52 weeks

Open-label extension period: 216 weeks

BID, twice daily; Hb, hemoglobin; SCPC, sickle cell pain crisis

Safety objective	Safety endpoint
To determine the effect of mitapivat vs placebo on:	Measured by:
Safety	Type, severity, and relationship to study drug of AEs and serious AEs
AE, adverse event

- advisory board member. AC: Agios, bluebird bio, Cheisi, Novartis, Vertex - consultancy;

bluebird bio, Forma-Novo Nordisk, Novartis, Pfizer - research funding. DSD: Agios, bluebird

bio, Novartis, Novo Nordisk, Pfizer - advisory board member. SaK: Emmaus, Novartis, Pfizer

- advisory committees; Agios, Pfizer - research funding. IMI: Agios - RISE UP trial clinical

advisory board member; Novo Nordisk - research funding. AO, SM, SG, KO, and AUZ: Agios

- employee and shareholder. JX: Agios - employee and shareholder, at the time of research.

RC: Addmedica, Agios, Forma Therapeutics, Novartis, Novo Nordisk, Pfizer, Vertex - advisory

board/consultancy.

downloadable poster are available via the QR code

This study was funded by Agios Pharmaceuticals, Inc. Presented at the 2024 European Hematology Association (EHA) Hybrid Congress, June 13-16, 2024, Madrid, Spain, and Virtual