OTQ923 / Novartis, Intellia Therap - LARVOL DELTA

Rheological Comparison of Red Cells from Individuals with SCD Treated with Gene Therapy, Haploidentical Transplantation or Hydroxyurea (ASH 2024) - P1, P1/2, P2, P3 | "Results : We compared the GT (CTX001, n=2, BB305, n=2, and sponsored clinical trial OTQ923, n=4), HaploHCT (n=4), and HU (n=15) groups. Post HaploHCT, individuals exhibited nearly normalized RBC rheology, with very similar inter-individual results. Further studies are needed to confirm our findings in a larger SCD patient cohort, including samples pre- and post-transplant; longer follow-up of both strategies are also needed."

Clinical • Gene therapy • Gene Therapies • Genetic Disorders • Hematological Disorders • Sickle Cell Disease • Transplantation • HBB

Long-term Follow-up (LTFU) of Patients Treated With Genome-edited Autologous Hematopoietic Stem and Progenitor Cells (HSPC) (clinicaltrials.gov) - P1 | N=4 | Active, not recruiting | Sponsor: Novartis Pharmaceuticals | Recruiting ➔ Active, not recruiting | Phase classification: P ➔ P1

Enrollment closed • Phase classification • Genetic Disorders • Hematological Disorders • Sickle Cell Disease

Study of Safety and Efficacy of Genome-edited Hematopoietic Stem and Progenitor Cells in Sickle Cell Disease (SCD) (clinicaltrials.gov) - P1 | N=4 | Terminated | Sponsor: Novartis Pharmaceuticals | Active, not recruiting ➔ Terminated; The decision of early termination was made due to business reasons and was not a consequence of any safety concern.

Trial termination • Genetic Disorders • Hematological Disorders • Sickle Cell Disease

Study of Safety and Efficacy of Genome-edited Hematopoietic Stem and Progenitor Cells in Sickle Cell Disease (SCD) (clinicaltrials.gov) - P1 | N=4 | Active, not recruiting | Sponsor: Novartis Pharmaceuticals | Trial completion date: Sep 2026 ➔ Oct 2024 | Trial primary completion date: Aug 2025 ➔ Oct 2024

Trial completion date • Trial primary completion date • Genetic Disorders • Hematological Disorders • Sickle Cell Disease

Long-term Follow-up (LTFU) of Patients Treated With Genome-edited Autologous Hematopoietic Stem and Progenitor Cells (HSPC) (clinicaltrials.gov) - P=N/A | N=5 | Recruiting | Sponsor: Novartis Pharmaceuticals | Not yet recruiting ➔ Recruiting

Enrollment open • Genetic Disorders • Hematological Disorders • Sickle Cell Disease

Long-term Follow-up (LTFU) of Patients Treated With Genome-edited Autologous Hematopoietic Stem and Progenitor Cells (HSPC) (clinicaltrials.gov) - P=N/A | N=5 | Not yet recruiting | Sponsor: Novartis Pharmaceuticals | Trial completion date: Jul 2025 ➔ Dec 2038 | Initiation date: Nov 2023 ➔ Feb 2024 | Trial primary completion date: Jul 2025 ➔ Dec 2038

Trial completion date • Trial initiation date • Trial primary completion date • Genetic Disorders • Hematological Disorders • Sickle Cell Disease

Study of Safety and Efficacy of Genome-edited Hematopoietic Stem and Progenitor Cells in Sickle Cell Disease (SCD) (clinicaltrials.gov) - P1 | N=5 | Active, not recruiting | Sponsor: Novartis Pharmaceuticals | Phase classification: P1/2 ➔ P1

Phase classification • Genetic Disorders • Hematological Disorders • Sickle Cell Disease

Long-term Follow-up (LTFU) of Patients Treated With Genome-edited Autologous Hematopoietic Stem and Progenitor Cells (HSPC) (clinicaltrials.gov) - P=N/A | N=5 | Not yet recruiting | Sponsor: Novartis Pharmaceuticals

New trial • Genetic Disorders • Hematological Disorders • Sickle Cell Disease

Study of Safety and Efficacy of Genome-edited Hematopoietic Stem and Progenitor Cells in Sickle Cell Disease (SCD) (clinicaltrials.gov) - P1/2 | N=5 | Active, not recruiting | Sponsor: Novartis Pharmaceuticals | Recruiting ➔ Active, not recruiting | N=20 ➔ 5 | Trial completion date: Oct 2025 ➔ Sep 2026

Enrollment change • Enrollment closed • Trial completion date • Genetic Disorders • Hematological Disorders • Sickle Cell Disease

CRISPR-Cas9 Editing of the HBG1 and HBG2 Promoters to Treat Sickle Cell Disease. (PubMed, N Engl J Med) - P1/2 | "CRISPR-Cas9 disruption of the HBG1 and HBG2 gene promoters was an effective strategy for induction of fetal hemoglobin. Infusion of autologous OTQ923 into three participants with severe sickle cell disease resulted in sustained induction of red-cell fetal hemoglobin and clinical improvement in disease severity. (Funded by Novartis Pharmaceuticals; ClinicalTrials.gov number, NCT04443907.)."

Journal • Genetic Disorders • Hematological Disorders • Sickle Cell Disease • Transplantation • CD34 • HBG2

Treatment of Individuals with Severe Sickle Cell Disease with OTQ923, an Autologous, Ex Vivo, CRISPR/Cas9-Edited, CD34+ Hematopoietic Stem and Progenitor Cell Product, Leads to Durable Engraftment and Fetal Hemoglobin Induction (ASH 2022) - P1/2 | "OTQ923 was manufactured from cryopreserved, peripheral blood derived CD34+ cells, collected after plerixafor mobilization...Participant 2 is a 21-year-old male with a history of ACS, and a silent cerebral infarct and was receiving hydroxyurea... Preliminary data demonstrate clinically meaningful increases in HbF and evidence of benefit for both Participants 1 and 2 after OTQ923 infusion. Edited alleles were stable and maintained in the peripheral blood for >6 mos. The safety profile of OTQ923 was as expected after myeloablative busulfan and autologous hematopoietic stem cell transplantation."

Preclinical • Bone Marrow Transplantation • Cardiovascular • Genetic Disorders • Hematological Disorders • Sickle Cell Disease • Transplantation • BCL11A • CD34

CRISPR/Cas9 Genome-Edited Autologous Hematopoietic Stem Cell Transplantation Therapies for Sickle Cell Disease (ASH 2022) - "We have developed 2 genome editing strategies targeting BCL11A for the induction of HbF levels and report the preclinical development of two potentially curative CRISPR/Cas9 ex-vivo genome-edited autologous hematopoietic stem cell therapies: HIX763 and OTQ923. Finally, a comparability assessment of OTQ923 produced using the research process and the clinical manufacturing process showed comparability in the quality of cells, as measured by off-target editing, genomic rearrangement, cell viability, editing efficiency, HbF induction, and in vivo engraftment. Together these studies demonstrate that the preclinical data adequately reflects the behavior of the cells intended for clinical use and supports advancing these drug products into clinical trials for the treatment of sickle cell disease."

Bone Marrow Transplantation • Genetic Disorders • Hematological Disorders • Oncology • Sickle Cell Disease • Transplantation • BCL11A

Study of Safety and Efficacy of Genome-edited Hematopoietic Stem and Progenitor Cells in Sickle Cell Disease (SCD) (clinicaltrials.gov) - P1/2 | N=20 | Recruiting | Sponsor: Novartis Pharmaceuticals | N=30 ➔ 20

Enrollment change • Genetic Disorders • Hematological Disorders • Sickle Cell Disease

Study of Safety and Efficacy of Genome-edited Hematopoietic Stem and Progenitor Cells in Sickle Cell Disease (SCD) (clinicaltrials.gov) - P1/2 | N=30 | Recruiting | Sponsor: Novartis Pharmaceuticals | Trial primary completion date: Dec 2023 ➔ Aug 2025

Trial primary completion date • Genetic Disorders • Hematological Disorders • Sickle Cell Disease

Study of Safety and Efficacy of Genome-edited Hematopoietic Stem and Progenitor Cells in Sickle Cell Disease (SCD) (clinicaltrials.gov) - P1/2 | N=30 | Recruiting | Sponsor: Novartis Pharmaceuticals | Trial completion date: Dec 2024 ➔ Aug 2025

Trial completion date • Genetic Disorders • Hematological Disorders • Sickle Cell Disease

Study of Safety and Efficacy of Genome-edited Hematopoietic Stem and Progenitor Cells in Sickle Cell Disease (SCD) (clinicaltrials.gov) - P1/2; N=30; Recruiting; Sponsor: Novartis Pharmaceuticals; Trial completion date: Dec 2023 ➔ Dec 2024

Clinical • Trial completion date • Genetic Disorders • Hematological Disorders • Sickle Cell Disease

Study of Safety and Efficacy of Genome-edited Hematopoietic Stem and Progenitor Cells in Sickle Cell Disease (SCD) (clinicaltrials.gov) - P1/2; N=30; Recruiting; Sponsor: Novartis Pharmaceuticals; N=20 ➔ 30

Clinical • Enrollment change • Genetic Disorders • Hematological Disorders • Sickle Cell Disease

Study of Safety and Efficacy of Genome-edited Hematopoietic Stem and Progenitor Cells in Sickle Cell Disease (SCD) (clinicaltrials.gov) - P1/2; N=20; Recruiting; Sponsor: Novartis Pharmaceuticals; Not yet recruiting ➔ Recruiting; N=30 ➔ 20

Clinical • Enrollment change • Enrollment open • Genetic Disorders • Hematological Disorders • Sickle Cell Disease

Study of Safety and Efficacy of Genome-edited Hematopoietic Stem and Progenitor Cells in Sickle Cell Disease (SCD) (clinicaltrials.gov) - P1/2; N=30; Not yet recruiting; Sponsor: Novartis Pharmaceuticals

Clinical • New P1/2 trial • Gene Therapies • Genetic Disorders • Hematological Disorders • Sickle Cell Disease

FDA Accepts Investigational New Drug Application for CRISPR/Cas9-Based Sickle Cell Disease Therapeutic Candidate Developed Under Collaboration with Intellia Therapeutics (GlobeNewswire, Intellia Therapeutics, Inc.) - "Intellia Therapeutics...announced that the U.S. Food and Drug Administration (FDA) has accepted the Investigational New Drug (IND) application submitted by its collaborator, Novartis, for a CRISPR/Cas9-based engineered cell therapy for the treatment of sickle cell disease (SCD). This Phase 1/2 clinical trial will begin investigating OTQ923 in adult patients with severe complications of SCD. OTQ923 is a SCD treatment based on genome editing of hematopoietic stem cells (HSCs), using CRISPR/Cas9 RNA guides identified through Intellia’s cell therapy research collaboration with Novartis."

IND • New P1/2 trial

GENERATION OF A LIBRARY OF WT1-SPECIFIC T-CELL RECEPTORS (TCR) FOR CRISPR-EDITED TRANSGENIC TCR T-CELL THERAPY WITH ACTIVITY AGAINST ACUTE MYELOID LEUKEMIA (EBMT 2020) - "Simultaneous editing of the endogenous TCR α and β chains using CRISPR/Cas9 technology (knock-out efficiency >90%), followed by transduction of T-cells with a lentiviral vector encoding the WT1-specific TCR (initially focusing on the most common HLA class I alleles), led to the expression of the inserted TCR in >95% of CD8+T-lymphocytes. In summary, we established a protocol enabling consistent and efficient tumor-specific TCR hunting, identification and characterization. TCR genes can be easily and rapidly used to redirect T-cell specificity against cancer cells by TCR gene editing."

IO Biomarker • CASP3 • CD8 • IFNG

Genomic screening reveals UBA1 as a potent and druggable target in diverse models of triple negative breast cancer (SABCS 2019) - "We took advantage of this system to ask whether it may identify new druggable targets to treat TNBC and performed whole genome CRISPR/cas9 screening in two TNBC cell lines, BT549 and MDA-MB-468...TAK-243 induced tumor regressions in two PDX models of TNBC. Overall, these data demonstrate UBA1 is a novel drug target in TNBC."

First-in-Human Assessment of Feasibility and Safety of Multiplexed Genetic Engineering of Autologous T Cells Expressing NY-ESO -1 TCR and CRISPR/Cas9 Gene Edited to Eliminate Endogenous TCR and PD-1 (NYCE T cells) in Advanced Multiple Myeloma (MM) and Sarcoma. (PubMed, Blood) - "Fraietta:Tmunity: Research Funding; Cabaletta: Research Funding; LEK Consulting: Consultancy. Hexner:novartis: Research Funding. June:Novartis: Research Funding; Tmunity: Other: scientific founder, for which he has founders stock but no income, Patents & Royalties."

Journal

"Díky mechanismu CRISPR-Cas9 umíme od roku 2016 celkem jednoduše upravovat DNA dle potřeby. @FuturePortPRG @Novartis #technologie #zdravotnictvi @automatizace #digitalizace #zdravi #lecba @ZdravotniciSOS #modernitechnologie #robotizace #cesko #dna #CR https://t.co/vUzeL2TNFW" (@zdravezpravy)

Delivering cellular and gene therapies to patients: solutions for realizing the potential of the next generation of medicine. (PubMed, Gene Ther) - "The Food and Drug Administration approved the U.S.'s first gene therapy, Novartis' tisagenlecleucel, and technologies like CRISPR-Cas9 are poised to create a wave of new medicines. This paper reviews the existing system to deliver cell and gene therapies and outlines the requirements to make them accessible to patients. Informed by interviews with experts, opportunities for improvement are identified along the patient and cell journeys, and a call to action is made for stakeholders to detail and implement change."

Clinical • Journal • Review