Study of Safety and Efficacy of Genome-edited Hematopoietic Stem and Progenitor Cells in Sickle Cell Disease (SCD)

A First-in-patient Phase I/II Clinical Study to Investigate the Safety, Tolerability and Efficacy of Genome-edited Hematopoietic Stem and Progenitor Cells in Subjects With Severe Complications of Sickle Cell Disease

This study evaluated a genome-edited, autologous, hematopoietic stem and progenitor cell (HSPC) product - OTQ923 to reduce the biologic activity of BCL11A, increasing fetal hemoglobin (HbF) and reducing complications of sickle cell disease.

Study Overview

• Status: Terminated
• Conditions: Sickle Cell Disease
• Intervention / Treatment: Biological: OTQ923; Biological: OTQ923

Detailed Description

CADPT03A12101 was a multicenter, multi-part, first-in-human, proof-of-concept, open label non-randomized, clinical study in Sickle Cell Disease (SCD) subjects. This study included apheresis of mobilized hematopoietic stem and progenitor cells (HSPCs), ex vivo CRISPR/Cas9-mediated genome editing and expansion, followed by myeloablative conditioning and autologous hematopoietic stem cell transplant (HSCT) with follow-up for a minimum of one year and up to two years.

The study was divided into the following parts:

• Part A - Adult subjects were dosed with OTQ923.
• Part B - Assessment of OTQ923 in pediatric patients, however Part B was not opened.

• Study Type: Interventional
• Enrollment (Actual): 4
• Phase: Phase 1

Contacts and Locations

Study Locations

• United States
  • Illinois
    • Chicago, Illinois, United States, 60637
      • University of Chicago
  • New York
    • New York, New York, United States, 10065
      • Memorial Sloan Kettering Cancer Ctr
  • Tennessee
    • Memphis, Tennessee, United States, 38105-3678
      • St Jude Children's Research Hospital

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 2 years to 40 years (Child, Adult)
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

1. Male or female subjects age 2-40 years inclusive
2. Confirmed diagnosis of sickle cell disease with globin typing (e.g. HbSS, HbSC, HbS/β0-thalassemia or others)
3. Performance status >70% (Karnofsky for subjects >16 years of age and Lansky for subjects <16 years of age)
4. At least one of the following indicators of disease severity as defined in the protocol - Vaso-occlusive pain crisis, Acute chest syndrome, Recurrent priapism, prior stroke, receive chronic transfusions, Red cell alloimmunization
5. Subjects, who have failed, not tolerated or refused hydroxyurea therapy.

Exclusion Criteria:

1. Available matched related donor for HSCT
2. Clinically significant active infection
3. Seropositive for HIV or HTLV
4. Active known malignancy, myelodysplasia, abnormal cytogenetics or immunodeficiency
5. Prior HSCT or gene therapy
6. Known hepatic cirrhosis, bridging hepatic fibrosis or active hepatitis
7. Protocol defined iron overload
8. Cerebrovascular procedure within one year, including pial synangiosis for Moyamoya
9. Severe or progressive arteriopathy or cerebrovascular disease, including Moyamoya

Other protocol defined inclusion/exclusion criteria may apply

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: OTQ923; Single intravenous infusion of OTQ923 Part A - Adults treated with OTQ923; Part B - Children age 2-17 treated with OTQ923 based on review of data from Part A by Health agency after a formal interim analysis.	Biological: OTQ923; Single intravenous infusion of OTQ923 cell suspension; Other Names: Adult Part A; Biological: OTQ923; Single intravenous infusion of OTQ923, based on review of data from Part A by Health agencies after a formal interim analysis; Other Names: Children 2-17 years old - Part B

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Number of participants with adverse events and serious adverse events	Number of participants with adverse events (AEs) and serious adverse events (SAEs), including changes from baseline in vital signs, electrocardiograms and laboratory results qualifying and reported as AEs.	up to 24 months
Time to reach absolute neutrophil count (ANC) ≥500/μL for 3 consecutive days	Time to engraftment is defined as first of 3 consecutive days when an absolute neutrophil count (ANC) ≥500/μL after receiving OTQ923 was reached.	up to 24 months
Fetal hemoglobin (HbF) expression 6 months after hematopoietic stem cell transplant (HSCT)	Assessment of HbF expression will be done by measuring total fetal hemoglobin over time.	at 6 months

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Durability of hematologic engraftment	Engraftment durability/persistence by measuring the proportion of alleles with on-target CRISPR modification in peripheral blood (total white blood cells (WBC)) and bone marrow over time up to 24 months	up to 24 months
Proportion of subject to achieve 30% of total HbF at 12 months	Assessment of HbF expression will be done by measuring total fetal hemoglobin over time.	12 months
Time to achieve 30% total HbF	Assessment of HbF expression will be done by measuring total fetal hemoglobin over time.	up to 24 months
Time to peak total HbF	Assessment of HbF expression will be done by measuring total fetal hemoglobin over time.	up to 24 months
Percentage of edited WBC and bone marrow cells by time points	Assessment of in vivo cellular kinetics	up to 24 months
Number of participants with treatment induced anti-Cas9 humoral and cellular immunogenicity	To evaluate presence of pre-existing or treatment induced anti-Cas9 humoral and cellular immunogenicity	up to 24 months
Overall Survival	To evaluate the overall survival which is defined as the time from date of start of treatment to date of death to any cause.	up to 24 months
Transplant-related mortality	Assessment of mortality	up to 24 months
Evaluation of effect on patient-reported outcomes from baseline and post-HSCT with age appropriate patient reported measures	Determine health status following instruments ASCQ-ME emotional impact	up to 24 months
Number of participants with change from baseline of annualized VOC rate by 65%	The annualized rate at baseline will be compared to that of vaso-occlusive crises (VOC) at 12 months.	Baseline, 12 months
Number of participants with change from baseline of annualized SCD complications (aggregate of VOC, ACS, priapism and stroke) and if relevant, rate of transfusion by 65%	The annualized rate at baseline will be compared to that of aggregate Sickle Cell Disease (SCD) complications (VOC, acute chest syndrome (ACS), priapism, and stroke) and transfusions at 12 months.	Bseline, 12 months
Evaluation of effect on patient-reported outcomes from baseline and post-HSCT with age appropriate patient reported measures	Determine health status following instruments PROMIS fatique	up to 24 months
Evaluation of effect on patient-reported outcomes from baseline and post-HSCT with age appropriate patient reported measures	Determine health status following instruments PROMIS physical functioning	up to 24 months
Evaluation of effect on patient-reported outcomes from baseline and post-HSCT with age appropriate patient reported measures	Determine health status following instruments ASCQ-ME sleep impact	up to 24 months
Evaluation of effect on patient-reported outcomes from baseline and post-HSCT with age appropriate patient reported measures	Determine health status following instruments ASCQ-ME pain impact	up to 24 months

Collaborators and Investigators

• Sponsor: Novartis Pharmaceuticals

Publications and helpful links

General Publications

• Ligon JA, Cupit-Link MC, Yu C, Levine J, Foley T, Rotz S, Sharma A, Gomez-Lobo V, Shah NN. Pediatric Cancer Immunotherapy and Potential for Impact on Fertility: A Need for Evidence-Based Guidance. Transplant Cell Ther. 2024 Aug;30(8):737-749. doi: 10.1016/j.jtct.2024.06.006. Epub 2024 Jun 10.
• Sharma A, Young A, Carroll Y, Darji H, Li Y, Mandrell BN, Nelson MN, Owens CL, Irvine M, Caples M, Jerkins LP, Unguru Y, Hankins JS, Johnson LM. Gene therapy in sickle cell disease: Attitudes and informational needs of patients and caregivers. Pediatr Blood Cancer. 2023 Jun;70(6):e30319. doi: 10.1002/pbc.30319. Epub 2023 Mar 28.
• Persaud Y, Mandrell BN, Sharma A, Carroll Y, Irvine M, Olufadi Y, Kang G, Hijano DR, Rai P, Hankins JS, Johnson LM. Attitudes toward COVID-19 vaccine among pediatric patients with sickle cell disease and their caregivers. Pediatr Blood Cancer. 2023 May;70(5):e30274. doi: 10.1002/pbc.30274. Epub 2023 Mar 1.
• Sharma A, Boelens JJ, Cancio M, Hankins JS, Bhad P, Azizy M, Lewandowski A, Zhao X, Chitnis S, Peddinti R, Zheng Y, Kapoor N, Ciceri F, Maclachlan T, Yang Y, Liu Y, Yuan J, Naumann U, Yu VWC, Stevenson SC, De Vita S, LaBelle JL. CRISPR-Cas9 Editing of the HBG1 and HBG2 Promoters to Treat Sickle Cell Disease. N Engl J Med. 2023 Aug 31;389(9):820-832. doi: 10.1056/NEJMoa2215643.
• Bhoopalan SV, Yen JS, Levine RM, Sharma A. Editing human hematopoietic stem cells: advances and challenges. Cytotherapy. 2023 Mar;25(3):261-269. doi: 10.1016/j.jcyt.2022.08.003. Epub 2022 Sep 17.

Helpful Links

• CADPT03A12101 Clinical Trial Results Form
• A Plain Language Trial Summary is available on www.novctrd.com

Study record dates

Study Major Dates

• Study Start (Actual): August 25, 2020
• Primary Completion (Actual): January 6, 2025
• Study Completion (Actual): January 6, 2025

Study Registration Dates

• First Submitted: April 29, 2020
• First Submitted That Met QC Criteria: June 19, 2020
• First Posted (Actual): June 23, 2020

Study Record Updates

• Last Update Posted (Estimated): January 8, 2026
• Last Update Submitted That Met QC Criteria: January 6, 2026
• Last Verified: January 1, 2026

More Information

Terms related to this study

• Keywords: Gene therapy; autologous transplant; sickle cell; BCL11A; genome-edited hematopoietic stem and progenitor cellular therapy
• 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
• Other Study ID Numbers: CADPT03A12101; 2019-003489-41 (EudraCT Number)

Plan for Individual participant data (IPD)

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

IPD Plan Description

Novartis is committed to sharing access to patient-level data and supporting clinical documents from eligible studies with qualified external researchers. Requests are reviewed and approved by an independent review panel on the basis of scientific merit. All data provided is anonymized to protect the privacy of patients who have participated in the trial in line with applicable laws and regulations.

This trial data availability is according to the criteria and process described on www.clinicalstudydatarequest.com

Drug and device information, study documents

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