A Study Evaluating the Efficacy and Safety of Mitapivat (AG-348) in Participants With Sickle Cell Disease (RISE UP)

A Phase 2/3, Double-Blind, Randomized, Placebo-Controlled, Multicenter Study to Evaluate the Efficacy and Safety of Mitapivat in Subjects With Sickle Cell Disease

This clinical trial is a Phase 2/3 study that will determine the recommended dose of mitapivat and evaluate the efficacy and safety of mitapivat in sickle cell disease by testing how well mitapivat works compared to placebo to increase the amount of hemoglobin in the blood and to reduce or prevent the occurrence of sickle cell pain crises. In addition, the long-term effect of mitapivat on efficacy and safety will be explored in an open-label extension portion.

Study Overview

• Status: Active, not recruiting
• Conditions: Sickle Cell Disease
• Intervention / Treatment: Drug: Mitapivat; Other: Mitapivat-matching placebo; Other: Mitapivat-matching placebo

Detailed Description

Mitapivat is a small molecule, oral activator of pyruvate kinase R (PKR). PKR is involved with maintaining health, energy, and longevity of red blood cells (RBCs). The study aims to evaluate the efficacy and safety of treatment with mitapivat in participants with sickle cell disease. The study is a Phase 2/3 study in which the recommended dose of mitapivat will be selected and further evaluated. The Phase 2 portion includes a 12-week randomized, placebo-controlled period in which participants will be randomized in a 1:1:1 ratio to receive 2 dose levels of mitapivat or placebo. The Phase 3 portion includes a 52-week randomized, placebo-controlled period in which participants will be randomized in a 2:1 ratio to receive the recommended mitapivat dose level or placebo. Participants who complete either the Phase 2 or Phase 3 portion will have the option to move into a 216-week open label extension period to receive mitapivat.

• Study Type: Interventional
• Enrollment (Actual): 286
• Phase: Phase 2; Phase 3

Contacts and Locations

Study Locations

• Belgium
  • Antwerp, Belgium, 2030
    • ZAS Cadix
  • Liège, Belgium, 4000
    • CHR de la Citadelle
  • Liège, Belgium, 4000
    • Clinique CHC MontLégia
  • Brussels Capital
    • Anderlecht, Brussels Capital, Belgium, 1070
      • Hôpital Erasme
    • Edegem, Brussels Capital, Belgium, 2650
      • Universitair Ziekenhuis Antwerpen
• Brazil
  • Rio de Janeiro, Brazil, 20211-030
    • HEMORIO Instituto Nacional de Hematologia
  • São Paulo, Brazil, 05403-010
    • Hospital das Clínicas da Faculdade de Medicina da Universidad de São Paulo
  • Pernambuco
    • Recife, Pernambuco, Brazil, 50070-460
      • Multihemo Servicos Medicos S/A
  • Rio Grande do Sul
    • Porto Alegre, Rio Grande do Sul, Brazil, 90035-903
      • Hospital de Clinicas de Porto Alegre (HCPA) - PPDS
    • Porto Alegre, Rio Grande do Sul, Brazil, 90619-900
      • Hospital Sao Lucas Da Pontificia Universidade Catolica Do Rio Grande Do Sul (PUCRS)
  • São Paulo
    • Campinas, São Paulo, Brazil, 13083-878
      • Hospital de Clínicas da Unicamp
    • Ribeirão Preto, São Paulo, Brazil, 14051-140
      • Hospital Das Clínicas da Faculdade de Medicina de Ribeirão Preto - USP
    • Santo André, São Paulo, Brazil
      • Praxis Pesquisa Medica
• Canada
  • Ontario
    • Hamilton, Ontario, Canada, L8N 3Z5
      • McMaster University - St. Joseph's Healthcare Hamilton
    • Toronto, Ontario, Canada, M5G2C4
      • University Health Network
  • Quebec
    • Montreal, Quebec, Canada, H4A 3J1
      • McGill University Health Center
    • Montreal, Quebec, Canada, H2X 3E4
      • CHU Montreal
• France
  • Bouches-du-Rhône
    • Marseille, Bouches-du-Rhône, France, 13005
      • Hopitaux de La Timone
  • Gironde
    • Bordeaux, Gironde, France, 33000
      • Hôpital Pellegrin, CHU de Bordeaux
  • Guadeloupe
    • Pointe à Pitre, Guadeloupe, France, 97139
      • CHU Guadeloupe
  • Haute-Garonne
    • Toulouse, Haute-Garonne, France, 31059
      • Institut Universitaire du Cancer de Toulouse - Oncopole
  • Val-de-Marne
    • Créteil, Val-de-Marne, France, 94000
      • CHU Hôpital Henri Mondor
  • Île-de-France Region
    • Paris, Île-de-France Region, France, 75015
      • Hôpital Europeen Georges Pompidou
• Germany
  • Essen, Germany, 45147
    • Universitätsklinikum Essen
  • Regensburg, Germany, 93053
    • Universitätsklinikum Regensburg
• Israel
  • Afula, Israel, 18101
    • HaEmek Medical Center
  • Ḥeifā
    • Haifa, Ḥeifā, Israel, 31096
      • Rambam Medical Center
    • Safed, Ḥeifā, Israel, 13100
      • Ziv Medical Center
• Italy
  • Campania
    • Naples, Campania, Italy, 80131
      • A.O.R.N. "A. Cardarelli"
    • Naples, Campania, Italy, 80138
      • AOU dell'Universita degli Studi della Campania Luigi Vanvitelli
  • Emilia-Romagna
    • Modena, Emilia-Romagna, Italy, 41100
      • Azienda Ospedaliero Universitaria Di Modena Policlinico
  • Lazio
    • Rome, Lazio, Italy, 00165
      • IRCCS Ospedale Pediatrico Bambino Gesù - INCIPIT - PIN
  • Liguria
    • Genoa, Liguria, Italy, 16128
      • Ente Ospedaliero Ospedali Galliera
  • Sicily
    • Palermo, Sicily, Italy, 90146
      • Azienda Ospedaliera Ospedali Riuniti Villa Sofia-Cervello
• Kenya
  • Kisumu, Kenya, 40100
    • Kondele Children's Hospital
  • Kisumu, Kenya, 40100
    • Victoria Biomedical Research Institute (VIBRI)
  • Nairobi, Kenya, 00100
    • KEMRI CRDR Clinical Research Clinic Nairobi
  • Nairobi, Kenya, 00200
    • KEMRI/CRDR Siaya Clinical Research Annex
  • Nairobi, Kenya, 00200
    • Strathmore University
  • Nairobi, Kenya, 42325- 00100
    • Gertrude's Children's Hospital
  • Western
    • Kisumu, Western, Kenya, 40100
      • Kemri Usamru
• Lebanon
  • Beirut, Lebanon, 4407-2020
    • American University of Beirut Medical Center
  • Sidon, Lebanon, H96G+247
    • Hammoud Hospital University Medical Center
  • Beirut
    • Beirut, Beirut, Lebanon, 11-0236
      • American University of Beirut Medical Center
  • North Lebanon
    • Tarablus, North Lebanon, Lebanon, 1434
      • Nini Hospital
• Netherlands
  • Utrecht, Netherlands, 3584 CX
    • Universitair Medisch Centrum Utrecht
  • South Holland
    • Rotterdam, South Holland, Netherlands, 3015 GD
      • Erasmus MC
• Nigeria
  • Federal Capital Territory
    • Abuja, Federal Capital Territory, Nigeria, 900271
      • National Hospital Abuja
    • Abuja, Federal Capital Territory, Nigeria, 900271
      • University of Abuja Teaching Hospital
  • Lagos
    • Surulere, Lagos, Nigeria, 101014
      • Lagos University Teaching Hospital
• Oman
  • Musqal
    • Muscat, Musqal, Oman, H5QC+36M
      • Sultan Qaboos University Hospital, Hematology Department, COM&HS
• Saudi Arabia
  • Riyadh, Saudi Arabia, 1515 (KAIMRC)
    • King Abdullah International Medical Research Center
  • Ar Riya
    • Riyadh, Ar Riya, Saudi Arabia, 11472
      • King Khalid University Hospital
• Turkey (Türkiye)
  • Adana
    • Ankara, Adana, Turkey (Türkiye)
      • Hacettepe University
    • Ankara, Adana, Turkey (Türkiye), 06200
      • Hacettepe Universitesi Tip Fakultesi Hastanesi
    • Seyhan, Adana, Turkey (Türkiye), 01130
      • Acibadem Adana Hospital
• United Kingdom
  • Cambridge, United Kingdom, CB2 0QQ
    • Cambridge University Hospitals NHS Foundation Trust
  • London, United Kingdom, W12 0HS
    • Hammersmith Hospital
  • London, United Kingdom, SE5 9RS
    • King's College Hospital NHS Foundation Trust
  • London, United Kingdom, SE1 7EH
    • Guy's and St Thomas' NHS Foundation Trust
  • London, United Kingdom, WC1E 6BT
    • University College London Hospitals (UCLH)
  • Manchester, United Kingdom, M13 9WL
    • Manchester Royal Infirmary, Manchester University NHS Foundation Trust
  • City of London
    • London, City of London, United Kingdom, SE1 7EH
      • Evelina Children's Hospital
• United States
  • California
    • La Jolla, California, United States, 92037-1337
      • University of California San Diego
    • Los Angeles, California, United States, 90095-1678
      • UCLA Health
    • Oakland, California, United States, 94609
      • Children's Hospital Oakland
  • Connecticut
    • Farmington, Connecticut, United States, 06030-0001
      • University of Connecticut Health Center
  • District of Columbia
    • Washington D.C., District of Columbia, United States, 20010
      • Medstar Washington Hospital Center
    • Washington D.C., District of Columbia, United States, 20010-2916
      • Children's National Hospital
  • Florida
    • Miami, Florida, United States, 33101
      • Sylvester Comprehensive Cancer Center-Miami
  • Illinois
    • Chicago, Illinois, United States, 60637-1443
      • University of Chicago Medical Center
  • Indiana
    • Indianapolis, Indiana, United States, 46202-5109
      • Riley Hospital for Children
  • Louisiana
    • Shreveport, Louisiana, United States, 71103-4228
      • LSU Health Sciences Center - Shreveport
  • Maryland
    • Bethesda, Maryland, United States, 20814
      • National Heart Lung and Blood Institute
    • Largo, Maryland, United States, 20774-5374
      • Kaiser Permanente - Largo Medical Center
  • Massachusetts
    • Boston, Massachusetts, United States, 02114-2621
      • Massachusetts General Hospital
    • Boston, Massachusetts, United States, 02115-5724
      • Boston Children's Hospital
    • Boston, Massachusetts, United States, 02118
      • Boston Medical Center & Boston University School of Medicine
  • Michigan
    • Ann Arbor, Michigan, United States, 48109-5000
      • University of Michigan
    • Detroit, Michigan, United States, 48201
      • Children's Hospital of Michigan
  • Mississippi
    • Flowood, Mississippi, United States, 39232
      • Southern Specialty Clinic
    • Madison, Mississippi, United States, 39110-6115
      • Mississippi Center for Advanced Medicine
  • Nevada
    • Las Vegas, Nevada, United States, 89106
      • Cure 4 The Kids Foundation, A Division of Roseman University of Health Sciences
  • North Carolina
    • Greenville, North Carolina, United States, 27834
      • East Carolina University - Brody School of Medicine
  • Pennsylvania
    • Philadelphia, Pennsylvania, United States, 19104-5127
      • Penn Medicine - University of Pennsylvania Health System
    • Philadelphia, Pennsylvania, United States, 19134-1011
      • St. Christopher's Hospital for Children
  • Rhode Island
    • Providence, Rhode Island, United States, 02903
      • Lifespan at Rhode Island Hospital
  • Texas
    • Houston, Texas, United States, 77030
      • Texas Children's Hospital
    • Houston, Texas, United States, 77030-1501
      • University of Texas Health Science Center of Houston
  • Virginia
    • Richmond, Virginia, United States, 23298-5058
      • Virginia Commonwealth University
  • Washington
    • Seattle, Washington, United States, 98195
      • Seattle Cancer Care Alliance, University of Washington

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 16 years and older (Child, Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

• Age 16 years or older (18 years or older [France and Germany]); participants age 16 or 17 years must physically have completed puberty;
• Documented diagnosis of sickle cell disease (SCD) (HbSS, HbSC [combined heterozygosity for hemoglobins S and C], HbS/beta 0- thalassemia, HbS/ beta plus thalassemia, or other sickle cell syndrome variants);
• At least 2 SCPCs and no more than 10 SCPCs in the past 12 months;
• Hemoglobin at least 5.5 and 10.5 gram per deciliter (g/dL) at the most. Hemoglobin concentration must be based on an average of at least 2 Hb concentration measurements (separated by ≥7 days) collected during the Screening Period;
• If taking hydroxyurea, the hydroxyurea dose must be stable for at least 90 days before starting study drug. Discontinuation of hydroxyurea requires a 90-day washout prior to informed assent/consent;
• Women capable of becoming pregnant must agree to use 2 forms of contraception.

Exclusion Criteria:

• Pregnant, breastfeeding, or parturient;
• Receiving regularly scheduled transfusions;
• Hepatobiliary disorders including but not limited to significant liver disease or gallbladder disease;
• Severe kidney disease;
• Prior exposure to gene therapy or prior bone marrow or stem cell transplantation;
• Currently receiving treatment with a disease-modifying therapy for SCD (eg, voxelotor, crizanlizumab, L-glutamine), with the exception of hydroxyurea. The last dose of voxelotor, crizanlizumab, and L-glutamine must have been administered at least 90 days before randomization;
• Currently receiving treatment with hematopoietic stimulating agents; the last dose must have been administered at least 90 days before starting study drug;
• Received treatment on another investigational trial within 90 days prior to start of study drug or plans to participate in another investigational drug trial;
• Taking medications that are strong inhibitors of CYP3A4/5 or strong inducers of CYP3A4 that cannot be stopped in an acceptable timeframe before starting study drug (timeframe will be discussed with your doctor).

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Sequential Assignment
• Masking: Quadruple

Number of Arms

7

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Phase 2: Mitapivat 50 mg BID; Double-blind Period: Mitapivat 50 milligrams (mg) twice daily (BID) for 12 weeks.	Drug: Mitapivat; Mitapivat tablets; Other Names: AG-348; Mitapivat Sulfate
Experimental: Phase 2: Mitapivat 100 mg BID; Double-blind Period: Mitapivat 100 mg BID for 12 weeks.	Drug: Mitapivat; Mitapivat tablets; Other Names: AG-348; Mitapivat Sulfate
Placebo Comparator: Phase 2: Placebo; Double-blind Period: Mitapivat-matching placebo for 12 weeks.	Other: Mitapivat-matching placebo; Placebo to match 50 mg or 100 mg tablets; Other: Mitapivat-matching placebo; Placebo to match 100 mg tablets
Experimental: Phase 2: Open-Label Extension Period; Participants who received mitapivat 50mg BID in the double-blind period may choose to receive mitapivat 50mg BID for 216 weeks after. Participants who received mitapivat 100mg BID in the double-blind period may choose to receive mitapivat 100 mg BID for 216 weeks after. Participants who received mitapivat-matching placebo in the double-blind period, may be randomized to receive either mitapivat 50 mg or 100 mg BID for 216 weeks after.	Drug: Mitapivat; Mitapivat tablets; Other Names: AG-348; Mitapivat Sulfate
Experimental: Phase 3: Mitapivat 100 mg BID; Double-blind Period: Mitapivat 100 mg BID for 52 weeks.	Drug: Mitapivat; Mitapivat tablets; Other Names: AG-348; Mitapivat Sulfate
Placebo Comparator: Phase 3: Placebo; Double-blind Period: Mitapivat-matching placebo for 52 weeks.	Other: Mitapivat-matching placebo; Placebo to match 50 mg or 100 mg tablets; Other: Mitapivat-matching placebo; Placebo to match 100 mg tablets
Experimental: Phase 3: Open-Label Extension Period; Participants may choose to receive mitapivat 100 mg BID for 216 weeks after the Double-blind Period. Participants who received mitapivat-matching placebo in the double-blind period, may choose to receive mitapivat 100 mg BID for 216 weeks after the Double-blind Period.	Drug: Mitapivat; Mitapivat tablets; Other Names: AG-348; Mitapivat Sulfate

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Time Frame
Phase 2: Percentage of Participants With Hemoglobin (Hb) Response	Week 12
Phase 2: Percentage of Participants With Treatment-Emergent Adverse Events (AEs) and Treatment-Emergent Serious AEs (SAEs)	Up to Week 12
Phase 3: Percentage of Participants With Hb Response	Week 52
Phase 3: Annualized Rate of Sickle Cell Pain Crises (SCPCs)	Up to Week 52

Secondary Outcome Measures

Outcome Measure	Time Frame
Phase 2: Change From Baseline in Hb Concentration	Baseline, Week 10 up to Week 12
Phase 2: Change From Baseline in Indirect Bilirubin	Baseline, Week 10 up to Week 12
Phase 2: Change From Baseline in Lactate Dehydrogenase (LDH)	Baseline, Week 10 up to Week 12
Phase 2: Change From Baseline in Absolute Reticulocytes Count	Baseline, Week 10 up to Week 12
Phase 2: Change From Baseline in Percent Reticulocytes	Baseline, Week 10 up to Week 12
Phase 2: Change From Baseline in Erythropoietin	Baseline, Week 10 up to Week 12
Phase 2: Change From Baseline in Patient-Reported Outcomes Measurement Information System® (PROMIS®) Fatigue 13a Short Form (SF) Score	Baseline, Week 10 up to Week 12
Phase 2: Annualized Rate of SCPCs	Up to Week 12
Phase 2: Pharmacokinetic/Pharmacodynamic Relationship: Evaluate the Exposure of Mitapivat to the Change in Adenosine Triphosphate (ATP) and 2,3-Diphosphoglycerate (2,3-DPG)	Day 1 up to Week 8
Phase 2: Mitapivat Concentration Over Time	Day 1 up to Week 8
Phase 2: Mitapivat Area Under the Concentration	Day 1 up to Week 8
Phase 2: Mitapivat Maximum (Peak) Concentration	Day 1 up to Week 8
Phase 3: Change From Baseline in Hb Concentration	Baseline, Week 24 up to Week 52
Phase 3: Change From Baseline in Indirect Bilirubin	Baseline, Week 24 up to Week 52
Phase 3: Change From Baseline in Percent Reticulocytes	Baseline, Week 24 up to Week 52
Phase 3: Change From Baseline in PROMIS® Fatigue 13a SF Scores	Baseline, Week 24 up to Week 52
Phase 3: Annualized Frequency of Hospitalizations for SCPC	Up to Week 52
Phase 3: Change From Baseline in LDH Concentration	Baseline, Week 24 up to Week 52
Phase 3: Change From Baseline in Absolute Reticulocytes	Baseline, Week 24 up to Week 52
Phase 3: Change From Baseline in Erythropoietin	Baseline, Week 24 up to Week 52
Phase 3: Percentage of Participants With Improvement in the Patient Global Impression of Severity (PGIS) -Fatigue	Baseline, Weeks 24, 28, 40, and 52
Phase 3: Percentage of Participants With Improvement in the Patient Global Impression of Change (PGIC) -Fatigue	Baseline, Weeks 24, 28, 40, and 52
Phase 3: Time to First SCPC	Up to Week 52
Phase 3: Time to Second SCPC	Up to Week 52
Phase 3: Annualized Rate of Hospitalization Days for SCPC	Up to Week 52
Phase 3: Annualized Rate of Emergency Room Visits for SCPC	Up to Week 52
Phase 3: Change From Baseline in 6-Minute Walk Test (6MWT)	Baseline, Week 52
Phase 3: Change From Baseline in PROMIS Pain Intensity	Baseline, Week 24 and 52
Phase 3: Change From Baseline in Adult Sickle Cell Quality of Life Measurement Information System (ASCQ-Me) Pain Impact	Baseline, Week 24 and 52
Phase 3: PGIC of Pain	Baseline, Week 52
Phase 3: Change From Baseline in PGIS of Pain	Baseline, Week 52
Phase 3: Percentage of Participants With Treatment-Emergent Adverse Events (AEs) and Treatment-Emergent Serious AEs (SAEs)	Up to 56 weeks
Phase 3: Pharmacokinetic/Pharmacodynamic Relationship: Evaluate the Exposure of Mitapivat to the Change in ATP and 2,3-DPG Levels	Day 1 up to Week 40
Phase 3: Mitapivat Concentration Over Time	Day 1 up to Week 40
Phase 3: Mitapivat Area Under the Concentration Curve	Day 1 up to Week 40
Phase 3: Mitapivat Maximum (Peak) Concentration	Day 1 up to Week 40

Collaborators and Investigators

• Sponsor: Agios Pharmaceuticals, Inc.

Publications and helpful links

General Publications

• Obadina M, Wilson S, Derebail VK, Little J. Emerging Therapies and Advances in Sickle Cell Disease with a Focus on Renal Manifestations. Kidney360. 2023 Jul 1;4(7):997-1005. doi: 10.34067/KID.0000000000000162. Epub 2023 May 31.
• Idowu M, Otieno L, Dumitriu B, Lobo CLC, Thein SL, Andemariam B, Nnodu OE, Inati A, Glaros AK, Bartolucci P, Colombatti R, Taher AT, Abboud MR, Darbari D, Ataga KI, Antmen AB, Kuo KHM, de Souza Medina S, Oluyadi A, Iyer V, Morris S, Yates AM, Shao H, Patil S, Urbstonaitis R, Zaidi AU, Gheuens S, Smith WR. Safety and efficacy of mitapivat in sickle cell disease (RISE UP): results from the phase 2 portion of a global, double-blind, randomised, placebo-controlled trial. Lancet Haematol. 2025 Jan;12(1):e35-e44. doi: 10.1016/S2352-3026(24)00319-3. Epub 2024 Dec 4.
• van Dijk MJ, Rab MAE, van Oirschot BA, Bos J, Derichs C, Rijneveld AW, Cnossen MH, Nur E, Biemond BJ, Bartels M, Jans JJM, van Solinge WW, Schutgens REG, van Wijk R, van Beers EJ. One-year safety and efficacy of mitapivat in sickle cell disease: follow-up results of a phase 2, open-label study. Blood Adv. 2023 Dec 26;7(24):7539-7550. doi: 10.1182/bloodadvances.2023011477.
• Conrey A, Asomaning N, Frey I, Charles RP, Lovins D, Xu JZ, Mendez-Marti S, Le K, Kruah B, Li Q, Dunkelberger E, Cellmer T, Yates A, Wind-Rotolo M, Huston C, Jeffries N, Eaton WA, Thein SL. Long-term mitapivat treatment is safe and efficacious in patients with sickle cell disease. Blood Red Cells Iron. 2025 Sep;1(2):100014. doi: 10.1016/j.brci.2025.100014. Epub 2025 Sep 11.

Study record dates

Study Major Dates

• Study Start (Actual): February 11, 2022
• Primary Completion (Actual): October 30, 2025
• Study Completion (Estimated): February 1, 2030

Study Registration Dates

• First Submitted: July 29, 2021
• First Submitted That Met QC Criteria: August 30, 2021
• First Posted (Actual): September 2, 2021

Study Record Updates

• Last Update Posted (Actual): May 29, 2026
• Last Update Submitted That Met QC Criteria: May 28, 2026
• Last Verified: May 1, 2026

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Genetic Diseases, Inborn; Hematologic Diseases; Anemia, Hemolytic, Congenital; Anemia, Hemolytic; Anemia; Hemoglobinopathies; Congenital, Hereditary, and Neonatal Diseases and Abnormalities; Hemic and Lymphatic Diseases; Anemia, Sickle Cell; Molecular Mechanisms of Pharmacological Action; Enzyme Activators; mitapivat
• Other Study ID Numbers: AG348-C-020; 2021-001674-34 (EudraCT Number)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No