Casgevy (exagamglogene autotemcel) / Vertex, CRISPR Therap, Molecular Templates - LARVOL DELTA

Third-generation novel technologies for gene editing. (PubMed, Trends Biotechnol) - "CRISPR-Cas methods using RNA-guided enzymes are the most used gene editing tools and have produced gene-edited crops (rice, wheat, corn, etc.) and human therapeutics (Casgevy, approved for commercial use; Vertex Pharmaceuticals)...Some of these limitations were partially addressed by the development of second-generation editors, including base editors (BEs) and prime editors (PEs). Third-generation gene editing technologies such as seekRNA and bridgeRNA can overcome most of these limitations and are the subject of this review."

Journal • Review

CRISPR Technology in Disease Management: An Updated Review of Clinical Translation and Therapeutic Potential. (PubMed, Cell Prolif) - "This potential was affirmed with the FDA's first approval of a CRISPR-based therapy, Casgevy, for sickle cell disease in 2023...Despite these advances, significant challenges remain, including off-target effects, delivery methodologies, immune responses, and long-term genomic safety concerns. Future improvements in editor precision, innovative delivery platforms, and enhanced safety assessments will be essential to fully integrate CRISPR-based interventions into standard clinical practice, significantly advancing personalised medicine."

IO biomarker • Journal • Review • Alzheimer's Disease • CNS Disorders • Gene Therapies • Genetic Disorders • Hematological Disorders • Hematological Malignancies • Huntington's Disease • Infectious Disease • Movement Disorders • Muscular Dystrophy • Novel Coronavirus Disease • Oncology • Respiratory Diseases • Sickle Cell Disease • Solid Tumor • PD-1

Updated Review of Current Therapeutic Approaches for the Management of Sickle Cell Disease. (PubMed, Cardiovasc Hematol Disord Drug Targets) - "There are six Food and Drug Administration (FDA)-approved drugs, hydroxyurea, L-glutamine, crizanlizumab- TMCA, voxelotor, Casgevy, and Lyfgenia, that are used for the prophylaxis and treatment of serious complications of sickle cell disease. Ongoing research seeks to enhance treatment options and develop potential cures for SCD. This review attempts to present a comprehensive overview of the current therapeutic approaches and newly developed innovative medicines to combat and potentially eradicate SCD with an emphasis on their mechanisms, efficacy, and clinical implications."

Journal • Bone Marrow Transplantation • Gene Therapies • Genetic Disorders • Hematological Disorders • Infectious Disease • Pain • Sickle Cell Disease • Transplantation

CRISPR-based therapeutic genome editing for inherited blood disorders. (PubMed, Nat Rev Drug Discov) - "This paradigm has been exemplified with the first US Food and Drug Administration (FDA)-approved CRISPR-Cas9 therapy for sickle cell disease and β-thalassaemia, exa-cel (Casgevy)...In this Review, we explore the state-of-the-art genome editing technologies of nucleases, base editors and prime editors, which hold promise to address unmet clinical needs for patients with inherited haematological disorders. We highlight the progress made for several disorders and discuss the challenges that remain for ex vivo and in vivo targeting of HSCs for next-generation gene therapies."

Journal • Review • Beta-Thalassemia • Gene Therapies • Genetic Disorders • Hematological Disorders • Immunology • Sickle Cell Disease • Transplantation

Evaluation of Efficacy and Safety of a Single Dose of Exa-cel in Participants With Severe Sickle Cell Disease, βS/βC Genotype (clinicaltrials.gov) - P3 | N=12 | Not yet recruiting | Sponsor: Vertex Pharmaceuticals Incorporated | Trial completion date: Dec 2029 ➔ Dec 2033 | Trial primary completion date: Dec 2029 ➔ Dec 2033

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

MAXIMIZING SAFETY AND EFFICACY IN HEMATOPOIETIC STEM CELLS GENE THERAPY (EHA 2025) - "Background: Although therapies for HSC gene therapy have been recently approved (Zynteglo™, Lyfgenia™ and Casgevy®), still certain challenges remain associated with high costs, scalability and safety related to leukemic events. Based on these results, we propose a combined strategy of transduction enhancers and the use of Baboon envelope pseudotyped LV on the automated CliniMACS Prodigy platform to achieve significantly higher transduction efficiencies and enhanced engraftment."

Clinical • Gene therapy • Gene Therapies • CD34 • FLT3

DURABLE CLINICAL BENEFITS AND IMPROVEMENT OF TISSUE IRON OVERLOAD WITH EXAGAMGLOGENE AUTOTEMCEL FOR TRANSFUSION-DEPENDENT THALASSEMIA (EHA 2025) - "CLIMB-111 pts then enroll in long-term follow-up study CLIMB-131 for up to 15 yrs of follow-up. Exa-cel demonstrated durable clinical benefit in adults and adolescents with TDT and a safety profile consistent with busulfan myeloablative conditioning and autologous transplant. After exa-cel infusion, storage iron can be successfully removed by IRT with no evidence of iron reaccumulation after cessation of IRT. This suggests that in addition to durable transfusion independence, exa-cel has the potential to prevent tissue iron deposition, eliminating the need for chronic IRT, and may preserve end-organ function."

Clinical • Beta-Thalassemia • Genetic Disorders • Hematological Disorders

DURABLE CLINICAL BENEFITS WITH EXAGAMGLOGENE AUTOTEMCEL FOR SICKLE CELL DISEASE WITH RECURRENT VASO-OCCLUSIVE CRISIS AND FACTORS IMPACTING CD34+ HEMATOPOIETIC STEM CELL COLLECTION (EHA 2025) - "Exa-cel has the potential to provide a one-time functional cure for SCD. This is the largest data set analyzed to date describing single-agent plerixafor M/A collection characteristics of SCD pts. Younger age and blood CD34+ cells/µL at baseline and pre-apheresis correlated most strongly with higher CD34+ HSPC collection; no evidence of correlation was observed for measures of disease severity or blood HbS level."

Clinical • Genetic Disorders • Hematological Disorders • Sickle Cell Disease • CD34 • CRP • HP

Progress in bringing CASGEVY to patients (Vertex Press Release) - "Through reimbursement agreements, Vertex has secured access for eligible SCD or TDT patients in multiple countries including Austria, Bahrain, England, the Kingdom of Saudi Arabia, Northern Ireland, Scotland, the United Arab Emirates, the United States and Wales. Vertex is continuing to work with government and reimbursement authorities globally to secure sustainable access for additional eligible patients."

Reimbursement • Anemia • Beta-Thalassemia • Sickle Cell Disease

Vertex Presents Longer-Term Data at the 2025 European Hematology Association (EHA) Congress Demonstrating Durability of CASGEVY and Provides Update on Expanding Global Access to CASGEVY (Vertex Press Release) - P1/2/3 | N=59 | CLIMB‑111 (NCT03655678) | P1/2/3 | N=63 | CLIMB‑121 (NCT03745287) | P3 | N=160 | CLIMB-131 (NCT04208529) | Sponsor: Vertex Pharmaceuticals Incorporated | "In SCD, 43/45 (95.6%) evaluable patients (those with at least 16 months of follow-up) were free from vaso-occlusive crises (VOCs) for at least 12 consecutive months (VF12) in CLIMB-121 and CLIMB-131 combined (95% CI: 84.9%, 99.5%). The mean duration of VOC-free was 35.0 months (range 14.4 to 66.2 months)...In TDT, 54/55 (98.2%) evaluable patients (those with at least 16 months of follow-up) achieved transfusion-independence for at least 12 consecutive months with a weighted average hemoglobin (Hb) of at least 9 g/dL (TI12) in CLIMB-111 and CLIMB-131 combined (95% CI: 90.3%, 100%). The mean duration of transfusion independence was 40.5 months (range 13.6 to 70.8 months)."

Clinical data • Anemia • Beta-Thalassemia • Sickle Cell Disease

Validation of Clinical-Grade Electroporation Systems for CRISPR-Cas9-Mediated Gene Therapy in Primary Hepatocytes for the Correction of Inherited Metabolic Liver Disease. (PubMed, Cells) - "Here, we explore the use of the clinical-grade electroporator, the MaxCyte ExPERT GTx, utilized in the first FDA-approved CRISPR therapy, Casgevy, and evaluate its potential in primary hepatocytes in terms of delivery efficiency and cell viability...After surgery, Fah-/- graft recipients were cycled off and on nitisinone to achieve independence from drug-induced Hpd inhibition, an indicator of HT1 disease correction...Mean donor cell engraftment was significantly higher in GTx-recipient mice compared to untransfected control recipients (97.9% and 81.6%, respectively). Our results indicate that the GTx system does not negatively impact hepatocyte functionality and engraftment potential, thereby demonstrating the promise of GTx electroporation in hepatocytes as a viable cell therapy for treating genetic diseases that affect the liver."

Journal • Gene Therapies • Genetic Disorders • Hepatology • Transplantation

Implementing the Generalized Risk-Adjusted Cost-Effectiveness (GRACE) Model for Sickle Cell Disease (SCD) - A Case Study. (PubMed, Value Health) - "The GRACE method offers a more comprehensive and precise estimation of societal value, leading to more efficient and equitable resource allocation. This study not only highlights the limitations of traditional CEA in capturing the total societal value of treatments for severe diseases, but also provides a roadmap for incorporating GRACE model elements into HTAs, thereby facilitating broader acceptance of innovative therapies that significantly enhance patient QoL."

HEOR • Journal • Gene Therapies • Genetic Disorders • Hematological Disorders • Sickle Cell Disease

Cleveland Clinic Children’s Among First Hospitals to Use Novel Gene Therapy to Treat Inherited Blood Disorders (Cleveland Clinic) - "Cleveland Clinic Children’s is among the first in the country to administer a new gene therapy to modify a patient’s blood-forming stem cells in patients with thalassemia. The one-time treatment can reduce or eliminate the need for ongoing blood transfusions."

Launch US • Beta-Thalassemia

A Targeted Literature Review of Value-Based Agreements (VBAs) for Cell and Gene Therapies in the United States (ISPOR 2025) - "The therapies with VBAs in place included: Beqvez, Casgevy, Hemgenix, Kymriah, Luxturna, Lyfgenia, Roctavian, Vyjuvek, Zolgensma, and Zynteglo... In this review, multiple VBAs for CGTs were identified across multiple disease areas. Most payers did not publicly disclose which outcomes measures the VBAs were assessing. Of those that did, outcomes assessed could be sourced from routine patient visits and/or adjudicated claims, placing no additional burden on providers to collect data for the sole purpose of the VBA."

Gene therapy • Review • Gene Therapies

Dual Cation Exchange coupled with Multi-Modal Chromatography Allows the Production of High-Purity and Low residuals cGMP-Grade Cas9 Nuclease for Cell Therapy Applications (ASGCT 2025) - "The applications of such gene editing tools nucleases are ever-expanding and were recently validated with the US FDA approval of Casgevy, the first gene editing therapy for the treatment of sickle cell disease...In addition, this purification approach could be applied to similar nucleases or other proteins with comparable physicochemical properties. Disease Focus of Abstract:None"

Genetic Disorders • Hematological Disorders • Sickle Cell Disease

Maximizing Safety and Efficacy in Hematopoietic Stem Cell Gene Therapy (ASGCT 2025) - "Although new treatments for hematopoietic stem cell (HSC) gene therapy have been recently approved for several diseases such as beta-thalassemia (Zynteglo), sickle cell disease (Lyfgenia and Casgevy), and adrenoleukodystrophy (Skysona), a certain number of challenges still remain such as the high costs and scalability associated with these therapies, as well as the increased safety concerns regarding the related leukemic events. Experiments to investigate the mechanisms involved in better performance of LV transduction on the automated platform, including detailed molecular analysis of gene expression pathways by Next Generation Sequencing (NGS), are ongoing. Disease Focus of Abstract:Other Other: Rare diseases of the blood such as (but not limited to) hemoglobinopathies"

Clinical • Gene therapy • Beta-Thalassemia • Gene Therapies • Genetic Disorders • Hematological Disorders • Rare Diseases • Sickle Cell Disease • CD34 • FLT3

Cost-Effectiveness of Gene Therapy for Sickle Cell Disease in Uganda: Tailoring High-Income Evidence to Uganda's Context (ASGCT 2025) - "To estimate lifetime SoC costs in Uganda, we employed a Markov model designed to simulate the progression of patients across three health states: (1) standard of care (SoC) without hydroxyurea, (2) SoC with fixed dose hydroxyurea, and (3) death...Application of lovo-cel (bluebird bio) or exa-cel (Vertex Therapeutics) gene therapy for SCD was targeted to the same patient populations for authorized use in the U.S. and Europe: eligible individuals with SCD aged 12 years and older who meet specific trial inclusion criteria...2023) is lower than the scaled cost of a SCD gene therapy product in this model, suggesting a profit margin is possible for a locally manufactured gene therapy product for the treatment of SCD in Uganda. Disease Focus of Abstract:Sickle Cell"

Cost effectiveness • Gene therapy • HEOR • Gene Therapies • Genetic Disorders • Hematological Disorders • Sickle Cell Disease • SCD

Constructs of Chemically Ligated Guide RNAs (LgRNA) for Precise Clustered Regularly Interspaced Short Palindromic Repeats (CRISPR) Gene Editing (ASGCT 2025) - "The clustered, regularly interspaced short palindromic repeats (CRISPR) gene editing has the potential to cure many diseases of unmet needs, as indicated by the first approval of CRISPR-edited medicine (Casgevy)...We expected LgRNA to be a critical component of CRISPR therapeutics, including prime editors and STAR editors. Disease Focus of Abstract:None"

Highly Efficient Gene-editing with SaCas9 and AsCas12a in Patient Hematopoietic Stem and Progenitor Cells for Treating Sickle Cell Disease (ASGCT 2025) - "Most advances in gene-editing therapies including the FDA-approved Casgevy have utilized S. pyogenes Cas9 (SpCas9)... We found that SaCas9 showed a higher rate of sickle mutation correction (53%) than SpCas9 (49%), resulting in increased adult hemoglobin (HbA) levels (81% vs. 75%) and fewer chromosomal rearrangements (5 vs. 11 sites detected by CAST-seq)."

Clinical • Genetic Disorders • Hematological Disorders • Sickle Cell Disease • HBB

High-Coverage Whole-Genome Sequencing Reveals Adverse CRISPR Editing Events in Human HSPCs Targeted by Therapeutic gRNAs (ASGCT 2025) - "Leveraging this technology, we conducted high-coverage WGS on CRISPR-edited human hematopoietic stem and progenitor cells (HSPCs) modified with CRISPR-ribonucleoprotein (RNP) complexes, with gRNAs used in clinical studies, including the Casgevy gRNA—the first FDA-approved CRISPR-based therapy...By enabling a streamlined, one-step, and comprehensive assessment of genomic integrity, WGS-based approach represents a major advancement in ensuring the safety of CRISPR-based cell therapeutics. Disease Focus of Abstract:Sickle Cell"

Adverse events • Whole genome sequencing • Oncology

In vivo Targeting of Hematopoietic Stem Cell Receptor cKit by Lentivirus Particles Pseudotyped with chimeric VSV-G proteins (ASGCT 2025) - "Casgevy, recently approved by FDA, is an ex vivo hematopoietic stem cell (HSC) editing treatment that uses CRISPR/Cas9 to disrupt the erythroid-specific enhancer region of BCL11A, thereby restoring fetal hemoglobin production in adults with SCD or transfusion dependent thalassemia (TDT)...Further studies are underway to explore the HSC targeting potential of alternate ligands and combinations of ligands displayed on the lentiviral surface. Disease Focus of Abstract:Hemoglobinopathies"

Preclinical • Beta-Thalassemia • Genetic Disorders • Hematological Disorders • Sickle Cell Disease

Assessing the Impact of Exagamglogene Autotemcel (Exa-cel) on Health Inequalities in Patients with Sickle Cell Disease in the United Kingdom and Canada (ISPOR 2025) - "In the UK and Canada, the DCEA methodology provides a quantitative approach to estimate how exa-cel may significantly lower health inequality, which is an important element for HTA bodies to incorporate into healthcare decision making."

Clinical • Gene Therapies • Genetic Disorders • Hematological Disorders • Sickle Cell Disease

Comparing Ex-Vivo and In-Vivo Administration in CRISPR-Based Gene Therapies for Beta-Thalassemia: A Cost-Effectiveness Analysis (ISPOR 2025) - "The ex-vivo CRISPR therapy exagamglogene autotemcel (exa-cel) was recently approved by the National Institute for Health and Care Excellence (NICE) under a managed access agreement... In-vivo CRISPR offers cost savings, reduced patient burden, and improved cost-effectiveness compared to ex-vivo therapy. However, these results depend on assumptions regarding in-vivo efficacy and safety. Future research should address uncertainties as in-vivo CRISPR trial data emerge."

Cost effectiveness • Gene therapy • HEOR • Preclinical • Beta-Thalassemia • Bone Marrow Transplantation • Gene Therapies • Genetic Disorders

Payment Models for Sickle-Cell Disease Gene Therapies in Colorado Medicaid: Real-World Data Analysis (ISPOR 2025) - "The introduction of exagamglogene autotemcel (exa-cel) and lovotibeglogene autotemcel (lovo-cel) required a comprehensive evaluation of potential payment strategies. The significance of real-world data was emphasized in identifying eligible patient populations and determining the actual costs of SoC. Furthermore, the analysis pointed out that the duration of contracts has a significant impact on financial outcomes."

Clinical • Gene therapy • Medicaid • Real-world • Real-world evidence • Reimbursement • US reimbursement • Gene Therapies • Genetic Disorders • Hematological Disorders • Sickle Cell Disease

Advances in Gene Therapy for Sickle Cell Disease: From Preclinical Innovations to Clinical Implementation and Access Challenges. (PubMed, CRISPR J) - "In this review, we discuss recent preclinical studies and clinical trials of gene and cell therapies, focusing on the progress of FDA-approved treatments like Lyfgenia and Casgevy. We also examine the many challenges, including accessibility, safety, and long-term efficacy, which continue to shape the future of SCD gene therapy."

Journal • Preclinical • Review • Bone Marrow Transplantation • Cardiovascular • Gene Therapies • Genetic Disorders • Hematological Disorders • Infectious Disease • Pain • Sickle Cell Disease • Transplantation • SCD