BIVV003 / Sangamo Therap, Sanofi - LARVOL DELTA

Long - Term Follow Up of Sickle Cell Disease and Beta-thalassemia Subjects Previously Exposed to BIVV003 or ST-400. (clinicaltrials.gov) - P=N/A | N=8 | Active, not recruiting | Sponsor: Sangamo Therapeutics | Enrolling by invitation ➔ Active, not recruiting | N=12 ➔ 8

Enrollment change • Enrollment closed • Beta-Thalassemia • Bone Marrow Transplantation • Gene Therapies • Genetic Disorders • Hematological Disorders • Sickle Cell Disease • Transplantation

003SCD101: A Study to Assess the Safety, Tolerability, and Efficacy of BIVV003 for Autologous Hematopoietic Stem Cell Transplantation in Patients With Severe Sickle Cell Disease (clinicaltrials.gov) - P1/2 | N=7 | Completed | Sponsor: Sangamo Therapeutics | Active, not recruiting ➔ Completed

Trial completion • Bone Marrow Transplantation • Genetic Disorders • Hematological Disorders • Hematological Malignancies • Sickle Cell Disease • Transplantation • HP

Zinc finger nuclease-mediated gene editing in hematopoietic stem cells results in reactivation of fetal hemoglobin in sickle cell disease. (PubMed, Sci Rep) - "Interim results from the Phase 1/2 PRECIZN-1 study demonstrated that BIVV003 was well-tolerated in seven participants with SCD, of whom five of the six with more than 3 months of follow-up displayed increased total hemoglobin and HbF, and no severe vaso-occlusive crises. Our data suggest BIVV003 represents a compelling and novel cell therapy for the potential treatment of SCD."

Journal • Genetic Disorders • Hematological Disorders • Sickle Cell Disease

Long - Term Follow Up of Sickle Cell Disease and Beta-thalassemia Subjects Previously Exposed to BIVV003 or ST-400. (clinicaltrials.gov) - P=N/A | N=12 | Enrolling by invitation | Sponsor: Sangamo Therapeutics | Trial completion date: Aug 2037 ➔ Jul 2038 | Trial primary completion date: Aug 2037 ➔ Jul 2038

Gene therapy • Trial completion date • Trial primary completion date • Beta-Thalassemia • Bone Marrow Transplantation • Gene Therapies • Genetic Disorders • Hematological Disorders • Sickle Cell Disease • Transplantation

003SCD101: A Study to Assess the Safety, Tolerability, and Efficacy of BIVV003 for Autologous Hematopoietic Stem Cell Transplantation in Patients With Severe Sickle Cell Disease (clinicaltrials.gov) - P1/2 | N=8 | Active, not recruiting | Sponsor: Sangamo Therapeutics | Recruiting ➔ Active, not recruiting | Trial completion date: Aug 2024 ➔ Jul 2025 | Trial primary completion date: Aug 2024 ➔ Jul 2025

Enrollment closed • Trial completion date • Trial primary completion date • Bone Marrow Transplantation • Genetic Disorders • Hematological Disorders • Hematological Malignancies • Sickle Cell Disease • Transplantation

ZINC FINGER NUCLEASE-MEDIATED DISRUPTION OF THE BCL11A ERYTHROID ENHANCER IN PLERIXAFOR MOBILIZED CD34+ CELLS RESULTS IN ENRICHED BIALLELEIC EDITING AND ALLELE-ADDITIVE INCREASES IN FETAL HEMOGLOBIN (EHA 2019) - P1/2; "This drug product, ST 400, is in a phase 1/2a clinical trial for transfusion-dependent BT (NCT03432364). Overall, our data revealed that ZFN-mediated disruption of BCL11A ESE resulted in enriched biallelic editing with highly replicable and on-target small indels and increases in HbF. Further characterization of BIVV003 showed that injection of plerixafor mobilized ZFN edited HSPCs into immune-deficient NBSGW mice resulted in robust long-term engraftment (21 weeks) without any impact on the number of HSPCs and their progeny, including erythrocytes.Conclusion These data support the potential efficacy and specificity of plerixafor mobilized ZFN-edited HSPCs as a novel cell therapy for SCD patients."

Interim Safety and Efficacy Results from a Phase 1/2 Study of Zinc Finger Nuclease-Modified Autologous Hematopoietic Stem Cells for Sickle Cell Disease (PRECIZN-1) (ASH 2022) - P1/2 | "The adverse events (AEs) reported were consistent with plerixafor mobilization and busulfan myeloablative conditioning. Three of the 4 subjects infused and with over 52 weeks of follow-up have had stable engraftment of ZFN-modified HSPCs resulting in sustained elevated HbF levels and absence of severe VOCs post-BIVV003 administration. A fifth subject received BIVV003 manufactured using an improved process that has shown in internal experiments to increase the number of ZFN-modified long-term progenitors in the drug product."

Clinical • P1/2 data • Genetic Disorders • Hematological Disorders • Sickle Cell Disease • BCL11A • CD34

Preliminary Safety and Efficacy Results from Precizn-1: An Ongoing Phase 1/2 Study on Zinc Finger Nuclease-Modified Autologous CD34+ HSPCs for Sickle Cell Disease (SCD) (ASH 2021) - P1/2 | "The AEs reported were consistent with plerixafor mobilization and busulfan myeloablation therapy. All 4 infused patients had no SCD related events including VOCs following SAR445136 infusion, as well as increases in total Hb, HbF, and %F cells, and clinical improvements in PROMIS-57 domains. SAR445136 is generally well tolerated in the 4 subjects infused to date, with no related AEs or SAEs reported."

Clinical • P1/2 data • CNS Disorders • Genetic Disorders • Hematological Disorders • Hepatology • Sickle Cell Disease • Sleep Disorder • CD34

Quantitative Systems Pharmacology Model of Sickle Cell Disease and Response to Gene Editing Therapy to Support Clinical Development of SAR445136 (BIVV003) (ASH 2021) - P1/2 | "The model is intended to provide both qualitative and quantitative support for the clinical development and competitive differentiation of SAR445136. For future development, the model can be expanded to include additional data representing the SCD bone marrow microenvironment to further explore patient heterogeneity."

Clinical • Anemia • Genetic Disorders • Hematological Disorders • Pain • Sickle Cell Disease • CD34

Preliminary Results of a Phase 1/2 Clinical Study of Zinc Finger Nuclease-Mediated Editing of BCL11A in Autologous Hematopoietic Stem Cells for Transfusion-Dependent Beta Thalassemia (ASH 2019) - P1/2; "After routine leukapheresis following mobilization with G-CSF and plerixafor, autologous collections are enriched for CD34+ cells and transfected with mRNA encoding ZFNs with binding sites flanking the GATA-binding region of BCL11A ESE. ST-400 product is infused following myeloablative busulfan conditioning... ST-400 is an ex vivo, ZFN-edited autologous HSC product for increased erythroid HbF expression in TDT. Two infused patients had rapid hematopoietic reconstitution following myeloablative conditioning, and both have elevated HbF levels following HSCGT. These data are preliminary, and additional patients and longer follow-up will be required to understand the safety and efficacy of this therapy."

Clinical • P1/2 data • CD34 • CSF3

Zinc Finger Nuclease-Mediated Disruption of the BCL11A Erythroid Enhancer Results in Enriched Biallelic Editing, Increased Fetal Hemoglobin, and Reduced Sickling in Erythroid Cells Derived from Sickle Cell Disease Patients (ASH 2019) - P1/2; "Previously, we reported successful ZFN-mediated editing of the BCL11A ESE and reactivation of HbF in both dual (granulocyte colony-stimulating factor (G-CSF) and plerixafor) and single plerixafor mobilized HSPCs (Holmes 2017, Moran 2018). Both related drug candidates, ST-400 and BIVV003, are currently in phase 1/2a clinical trials for transfusion-dependent BT (NCT03432364) and SCD (NCT03653247), respectively...Experiments in HSPCs from additional SCD donors are ongoing. Overall, our data have shown that ZFN-mediated disruption of BCL11A ESE results in enriched biallelic editing with on-target small indels, reactivates HbF and reduces sickling, supporting the potential efficacy and specificity of BIVV003 as a novel cell therapy for SCD."

Clinical

Ex Vivo Gene-Edited Cell Therapy for Sickle Cell Disease: Disruption of the BCL11A Erythroid Enhancer with Zinc Finger Nucleases Increases Fetal Hemoglobin in Plerixafor Mobilized Human CD34+ Cells (ASH 2018) - P1/2; "This drug product, ST-400, passed extensive safety testing and is currently in a phase 1/2a clinical trial for transfusion-dependent beta-thalassemia (ClinicalTrials.gov number NCT03432364). Overall, these data demonstrate potential efficacy of ZFN-edited HSPCs (BIVV003) as a novel cell therapy for SCD patients. Holmes et al., 2017 (ASH abstract) Fitzhugh et al., 2009 Lagresle-Peyrou et al., 2018 Hsieh and Tisdale, 2018 Yannaki et al., 2012"

Preclinical • Biosimilar • Gene Therapies • Hematological Disorders

Long - Term Follow Up of Sickle Cell Disease and Beta-thalassemia Subjects Previously Exposed to BIVV003 or ST-400. (clinicaltrials.gov) - P=N/A | N=12 | Enrolling by invitation | Sponsor: Sangamo Therapeutics | Recruiting ➔ Enrolling by invitation

Enrollment status • Gene therapy • Preclinical • Beta-Thalassemia • Bone Marrow Transplantation • Gene Therapies • Genetic Disorders • Hematological Disorders • Sickle Cell Disease • Transplantation

Utility of a Semi-Mechanistic Model in Ex Vivo Gene Therapy for Sickle Cell Disease to Predict Clinical Results: Preliminary Results from the PRECIZN-1 Study (ASGCT 2022) - P1/2 | "BIVV003 is a novel, non-viral gene therapy that uses a pair of zinc finger nucleases to disrupt BCL11A expression and increase HbF production to mimic the natural condition of HPFH. Stem cell treatment in SCD patients is only now emerging, thus available literature and in-house clinical data to support model validation is limited. Due to the small sample size and short follow up in the PRECIZN-1 study, the model may require further evaluation.Platelet levels indicated the degree of myeloablative conditioning (suppression of stem and progenitor cells pretreatment) and recovery rate of stem and progenitor cells. Model simulations indicate that conditioning affects HbF levels while RBC transfusion (post treatment) does not."

Preclinical • Gene Therapies • Genetic Disorders • Hematological Disorders • Sickle Cell Disease • Transplantation

PRECIZN-1: A Study to Assess the Safety, Tolerability, and Efficacy of BIVV003 for Autologous Hematopoietic Stem Cell Transplantation in Patients With Severe Sickle Cell Disease (clinicaltrials.gov) - P1/2 | N=8 | Recruiting | Sponsor: Bioverativ, a Sanofi company | Trial completion date: Dec 2024 ➔ Aug 2024 | Trial primary completion date: Dec 2024 ➔ Aug 2024

Trial completion date • Trial primary completion date • Bone Marrow Transplantation • Genetic Disorders • Hematological Disorders • Hematological Malignancies • Sickle Cell Disease • Transplantation • CD34 • HP

PRECIZN-1: A Study to Assess the Safety, Tolerability, and Efficacy of BIVV003 for Autologous Hematopoietic Stem Cell Transplantation in Patients With Severe Sickle Cell Disease (clinicaltrials.gov) - P1/2 | N=8 | Recruiting | Sponsor: Bioverativ, a Sanofi company | Trial completion date: May 2024 ➔ Dec 2024 | Trial primary completion date: May 2024 ➔ Dec 2024

Trial completion date • Trial primary completion date • Bone Marrow Transplantation • Genetic Disorders • Hematological Disorders • Hematological Malignancies • Sickle Cell Disease • Transplantation • CD34 • HP

An Observational Long-term Safety and Efficacy Follow-up Study After Ex-vivo Gene Therapy With BIVV003 in Severe Sickle Cell Disease (SCD) and ST-400 in Transfusion-dependent Beta-thalassemia (TDT) With Autologous Hematopoietic Stem Cell Transplant (clinicaltrials.gov) - P=N/A | N=13 | Recruiting | Sponsor: Bioverativ, a Sanofi company | Trial completion date: Mar 2043 ➔ Aug 2037 | Trial primary completion date: Mar 2043 ➔ Aug 2037

Preclinical • Trial completion date • Trial primary completion date • Beta-Thalassemia • Bone Marrow Transplantation • Gene Therapies • Genetic Disorders • Hematological Disorders • Sickle Cell Disease • Transplantation

An Observational Long-term Safety and Efficacy Follow-up Study After Ex-vivo Gene Therapy With BIVV003 in Severe Sickle Cell Disease (SCD) and ST-400 in Transfusion-dependent Beta-thalassemia (TDT) With Autologous Hematopoietic Stem Cell Transplant (clinicaltrials.gov) - P=N/A; N=13; Recruiting; Sponsor: Bioverativ, a Sanofi company; Not yet recruiting ➔ Recruiting

Enrollment open • Preclinical • Beta-Thalassemia • Bone Marrow Transplantation • Gene Therapies • Genetic Disorders • Hematological Disorders • Sickle Cell Disease • Transplantation

PRECIZN-1: A Study to Assess the Safety, Tolerability, and Efficacy of BIVV003 for Autologous Hematopoietic Stem Cell Transplantation in Patients With Severe Sickle Cell Disease (clinicaltrials.gov) - P1/2; N=8; Recruiting; Sponsor: Bioverativ, a Sanofi company; Trial completion date: Nov 2023 ➔ May 2024; Trial primary completion date: Nov 2023 ➔ May 2024

Clinical • Trial completion date • Trial primary completion date • Bone Marrow Transplantation • Genetic Disorders • Hematological Disorders • Hematological Malignancies • Sickle Cell Disease • Transplantation • CD34 • HP

An Observational Long-term Safety and Efficacy Follow-up Study After Ex-vivo Gene Therapy With BIVV003 in Severe Sickle Cell Disease (SCD) and ST-400 in Transfusion-dependent Beta-thalassemia (TDT) With Autologous Hematopoietic Stem Cell Transplant (clinicaltrials.gov) - P=N/A; N=13; Not yet recruiting; Sponsor: Bioverativ, a Sanofi company

New trial • Preclinical • Beta-Thalassemia • Bone Marrow Transplantation • Gene Therapies • Genetic Disorders • Hematological Disorders • Sickle Cell Disease • Transplantation

Effect of Photobiomodulation on Critical Swimming Velocity: A Randomized, Crossover, Double-Blind, and Placebo-Controlled Study. (PubMed, Int J Sports Physiol Perform) - "A PBM application prior to front crawl swimming test did not significantly modify the CV, ST, physiological factors of metabolic fatigue, perceptual, and front crawl stroke efficiency parameters in competition swimmers covering distances of 100, 200, and 400 m."

Clinical • Journal • Cardiovascular • Fatigue

Sangamo Announces EMA Releases Details Supporting Orphan Designation for BIVV003 for the Treatment of Sickle Cell Disease (Businesswire) - "Sangamo Therapeutics...announced that the European Medicines Agency’s Committee for Orphan Medicinal Products (COMP) released details supporting the Orphan Designation of BIVV003, an investigational ex vivo gene-edited cell therapy product candidate currently being evaluated for the treatment of sickle cell disease in the Phase 1/2 PRECIZN-1 study partnered with Sanofi. The Committee’s decision to grant Orphan Designation was based in part on early data from three patients that had 52 weeks, 13 weeks, and 29 days of follow-up, respectively."

Orphan drug • Anemia • Hematological Disorders • Sickle Cell Disease

PRECIZN-1: A Study to Assess the Safety, Tolerability, and Efficacy of BIVV003 for Autologous Hematopoietic Stem Cell Transplantation in Patients With Severe Sickle Cell Disease (clinicaltrials.gov) - P1/2; N=8; Recruiting; Sponsor: Bioverativ, a Sanofi company; Trial completion date: Apr 2023 ➔ Nov 2023; Trial primary completion date: Apr 2023 ➔ Nov 2023

Clinical • Trial completion date • Trial primary completion date • Genetic Disorders • Hematological Disorders • Hematological Malignancies • Sickle Cell Disease • Transplantation • CD34 • HP

BIVV003: Primary completion and completion of P1/2 PRECIZN-1 trial (NCT03653247) for sickle cell disease in April 2023 (Sanofi) - Q4 & FY2020 Results

Trial completion date • Trial primary completion date • Sickle Cell Disease

BIVV003: Data from P1/2 PRECIZN-1 trial (NCT03653247) for sickle cell disease in 2023 (Sanofi) - Q2 2020 Results

P1/2 data • Sickle Cell Disease