Hemgenix (etranacogene dezaparvovec-drlb) / uniQure, CSL Behring - LARVOL DELTA

Etranacogene dezaparvovec in haemophilia b: Report of 1ST patient receiving HEMGENIX® in Spain (ASH 2025) - "RESULTS A 41-year-old male with moderately severe HB (baseline FIX 1.8%) was on prophylaxis with eftrenonacog alfa (50 IU/kg weekly)...In our case, the patient's evolution follows the expected pattern: good initial response, mild and reversible liver enzyme elevation with use of prednisone, and satisfactory FIX levels. Immunosuppression is being adapted to clinical and laboratory evolution. We expect to present updated 6-month data at the ASH 2025 Congress."

Clinical • Gene Therapies • Hematological Disorders • Hemophilia • Hemophilia B • Hepatitis C • Infectious Disease • Rare Diseases • Rheumatology

Elevation of liver health biomarkers before and after etranacogene dezaparvovec gene therapy in hemophilia B: Associations with long-term clinical outcomes (ASH 2025) - P3 | "Although theone participant without baseline ALT elevation had a history of HIV, HBV, and HCV, the late ALT elevationwas assessed by the investigator as alcohol related. Late increases in ALT did not affect FIX activity inthese participants.Treatment-related transaminitis following M6 occurred in only one participant (ALT 1.2 ULN) at a singletimepoint in Y4, which resolved without sequelae.ConclusionFollowing a single dose of etranacogene dezaparvovec, participants with pre-dose elevated ALT/AST orpost-dose (CS-treated) ALT elevation maintained FIX expression (albeit lower in the ALT/CS group) andhad similar bleed reduction up to 4 years post-dose, compared to those without ALT elevations.Long-term liver deterioration following liver-targeted gene therapy was not observed over four years, noteven in those identified as potentially at risk due to subacute liver inflammation following vector delivery.These findings demonstrate that in cases of mild ALT/AST elevation..."

Biomarker • Clinical • Clinical data • Gene therapy • Fibrosis • Gene Therapies • Hematological Disorders • Hemophilia • Hemophilia B • Hepatitis B • Hepatitis C • Hepatology • Human Immunodeficiency Virus • Immunology • Infectious Disease • Inflammation • Liver Cirrhosis • Rare Diseases

End-of-study analysis of the HOPE-B trial confirms the durable efficacy and safety of etranacogene dezaparvovec hemophilia b gene therapy over 5 years (ASH 2025) - P3 | "The completed 5-year HOPE-B trial conclusively demonstrated that a single dose ofetranacogene dezaparvovec delivers sustained, robust, endogenous FIX Padua expression, significantlyreducing bleeding rates and the need for exogenous hemostatic support in most participants with severeor moderately severe hemophilia B. This gene therapy showed a favorable safety profile, with no late-onset AAV-related oncogenicity or hepatotoxicity observed. The positive benefit/risk ratio reported herehighlights etranacogene dezaparvovec as a transformative therapy for individuals with hemophilia B.Consenting HOPE-B participants will be monitored long-term until 15 years post-treatment in the IX-TEND3003 study."

Clinical • Gene therapy • Brain Cancer • CNS Tumor • Gene Therapies • Hematological Disorders • Hematological Malignancies • Hemophilia • Hemophilia B • Hepatocellular Cancer • Myelodysplastic Syndrome • Rare Diseases • Solid Tumor

Liver dysfunction in AAV-mediated Hemophilia B gene therapy: Mechanisms and management strategies. (PubMed, Blood Rev) - "Clinical trials involving Etranacogene Dezaparvovec, Fidanacogene Elaparvovec, and BBM-H901 (Dalnacogene Ponparvovec) reported transient elevations in liver enzymes, typically occurring 2-6 weeks post-infusion. The hepatic complications, while manageable, pose a risk to therapeutic efficacy and highlight the need for careful monitoring, early detection, and personalized immunosuppressive strategies. This review explores the mechanisms of AAV-induced liver dysfunction in gene therapy for Hemophilia B, with a focus on clinical manifestations, immune-mediated pathogenesis, and emerging approaches for mitigating liver-related adverse effects and providing clinical guidance."

Journal • Review • Gene Therapies • Hematological Disorders • Hemophilia • Hemophilia B • Hepatology • Liver Failure • Rare Diseases

Final Analysis of a Study of Etranacogene Dezaparvovec for Hemophilia B. (PubMed, N Engl J Med) - P3 | "Sustained endogenous factor IX expression and low annualized bleeding rates over a 5-year period were observed after an infusion of etranacogene dezaparvovec. (Funded by uniQure and CSL Behring; HOPE-B ClinicalTrials.gov number, NCT03569891.)."

Journal • Gene Therapies • Hematological Disorders • Hemophilia • Hemophilia B • Rare Diseases

Data Published in the New England Journal of Medicine Confirm the Long-term Durability and Safety of HEMGENIX (etranacogene dezaparvovec-drlb) Over Five Years (PRNewswire) - "The five-year follow-up analysis demonstrated: Durable Factor IX Activity: Mean factor IX activity levels were sustained at greater than 36% during years one through five post-infusion: mean factor IX levels of 41.5 IU/dL (n=50) at year one, 36.7 IU/dL (n=50) at year two, 38.6 IU/dL (n=48) at year three, 37.4 IU/dL (n=47) at year four, and 36.1 IU/dL (n=48) at year five. Sustained Bleed Protection: The mean adjusted annualized bleeding rate (ABR) for all bleeds was reduced by approximately 90% from the lead-in (4.16, n=54) compared to year five (0.40, n=51) post-infusion."

P3 data • Hemophilia B

Deconstructing gene therapy in hemophilia for the clinician. (PubMed, Hematology Am Soc Hematol Educ Program) - "After decades of research, gene therapy for hemophilia is now commercially available for both hemophilia A and B. Currently, two products, valoctocogene roxaparvovec (for hemophilia A) and etranacogene dezaparvovec (for hemophilia B), have been licensed following approval in the United States and several other countries. This review's aims are (1) to deconstruct gene therapy in hemophilia and provide a basic framework for understanding its components and processes, including the transgene, the vector, and the delivery systems, in order to help clinicians present gene therapy as a treatment option in a shared decision-making model, better understand the clinical data, and explain gene therapy to their patients; (2) to gain knowledge of the currently approved gene therapies for hemophilia A and B, including their eligibility and exclusion criteria and the range of expected outcomes; and (3) to comprehend the shared decision-making process for these therapies and their..."

Journal • Review • Gene Therapies • Hematological Disorders • Hemophilia • Hemophilia A • Hemophilia B • Rare Diseases

Long-term durability of rAAV gene therapy in hemophilia: Factor expression, clinical outcomes and underlying molecular mechanisms. (PubMed, Blood Rev) - "Approved therapies-valoctocogene roxaparvovec for hemophilia A and etranacogene dezaparvovec for hemophilia B-have demonstrated significant reductions in bleeding frequency and factor replacement requirements. Emerging strategies to enhance durability include next-generation vector design, codon optimization, gene editing technologies, and alternative delivery platforms. This review synthesizes current clinical evidence, biological understanding, and translational challenges, with an emphasis on strategies to optimize long-term efficacy of AAV-mediated gene therapy for hemophilia."

Clinical data • Journal • Review • Gene Therapies • Hematological Disorders • Hemophilia • Hemophilia A • Hemophilia B • Rare Diseases

First Real-World Experience Administering Etranacogene Dezaparvovec Gene Therapy for People with Hemophilia B (ASH 2023) - "By implementing early and iterative education and developing center-specific protocols, the Hemophilia Outreach Center was able to successfully administer etranacogene dezaparvovec-drlb. These elements are crucial to ensure smooth execution and optimal patient outcomes."

Clinical • Gene therapy • Real-world • Real-world evidence • Gene Therapies • Hematological Disorders • Hemophilia • Hemophilia B • Rare Diseases

Long-Term Bleeding Protection, Sustained FIX Activity, Reduction of FIX Consumption and Safety of Hemophilia B Gene Therapy: Results from the HOPE-B Trial 3 Years after Administration of a Single Dose of Etranacogene Dezaparvovec in Adult Patients with Severe or Moderately Severe Hemophilia B (ASH 2023) - P3 | "Long-term follow-up during the HOPE-B trial has shown that a single-dose of etranacogene dezaparvovec resulted in long-term endogenous FIX Padua expression and superior bleeding protection compared to FIX prophylaxis in participants without or with AAV NAb titer ≤1:678, with a favorable safety profile over 3 years post-administration."

Clinical • Gene therapy • Cardiovascular • Gastrointestinal Cancer • Gene Therapies • Hematological Disorders • Hemophilia • Hemophilia B • Hepatocellular Cancer • Oncology • Rare Diseases • Solid Tumor

Role of Pharmacy Professionals in Gene Therapy Based on Adeno-Associated Viruses: Treatment of Hemophilia as a Template of Care. (PubMed, Can J Hosp Pharm) - "Recently approved AAV-based treatments for hemophilia, such as etranacogene dezaparvovec and fidanacogene elaparvovec, could provide long-term benefits by targeting the genetic basis of the condition. Furthermore, pharmacy professionals can help address challenges such as financial obstacles, regulatory adherence, and ethical issues. Using their expertise in medication management, patient education, and health system processes, pharmacy professionals can enhance the safety, effectiveness, and accessibility of AAV-based gene therapies for hemophilia, ultimately leading to better patient outcomes."

Journal • Review • Gene Therapies • Genetic Disorders • Hematological Disorders • Hemophilia • Hemophilia A • Rare Diseases

In Vitro and In Vivo Potency Differences between AAVRh74var and AAV5 Vectors Encoding the Same High-Activity Human Factor IX Variant, FIX-R338L, Expression Cassette: Implications for Hemophilia B Gene Therapy (ASH 2024) - "The only other approved HB gene therapy (etranacogene dezaparvovec) utilizes the AAV5 capsid and is administered at a 40-fold higher dose (2×1013 gc/kg). Overall, the results demonstrate differences between the AAVRh74var and AAV5 capsids. This is consistent with fidanacogene elaparvovec (AAVRh74var) achieving clinically robust efficacy, despite a several-fold lower dose than AAV5-based gene therapies."

Gene therapy • Preclinical • Gene Therapies • Hematological Disorders • Hemophilia • Hemophilia B • Hepatocellular Cancer • Oncology • Rare Diseases • Solid Tumor

Development of an Ex Vivo Precision Gene Engineered B Cell Medicine That Produces Active and Sustained Levels of FIX for the Treatment of Hemophilia B (ASH 2023) - "More recently, an adeno-associated virus (AAV) vector-based gene therapy, etranacogene dezaparvovec, has been approved for some adults as a potential new option...The qPCR data confirms the expected biodistribution of FIX-expressing BeCMs, which engraft and persist in bone marrow tissue over time. In summary, we have developed an ex vivo precision gene engineered B cell medicine that produces active and sustained levels of FIX for the treatment of hemophilia B. The potential therapeutic application of this unique biologic delivery system could afford a novel treatment modality for hemophilia B."

Preclinical • Gene Therapies • Hematological Disorders • Hemophilia • Hemophilia B • Pediatrics • Rare Diseases

Adult Patients with Hemophilia B and with a History of Chronic HCV/HBV Infection Receiving Liver-Directed Gene Therapy Demonstrated Long-Term Bleeding Protection and Sustained FIX Activity: Efficacy and Safety Results from the HOPE-B Trial 3 Years after Administration of a Single Dose of Etranacogene Dezaparvovec (ASH 2023) - P2 | "The majority of HOPE-B trial participants were adults with a history of chronic HCV and/or HBV infection without active viral disease or evident pre-existing liver fibrosis. Safety and efficacy are observed in the HCBV participants."

Clinical • Gene therapy • Fibrosis • Gastrointestinal Cancer • Gene Therapies • Hematological Disorders • Hemophilia • Hemophilia B • Hepatitis B • Hepatitis C • Hepatocellular Cancer • Hepatology • Human Immunodeficiency Virus • Immunology • Infectious Disease • Liver Cirrhosis • Oncology • Rare Diseases • Solid Tumor • AFP • CD4

HIV Comorbid Infection and Liver-Directed AAV-Based Gene Therapy in Adults with Severe and Moderately Severe Hemophilia B: Efficacy and Safety Results from Phase 2b and the Pivotal Phase 3 HOPE-B Trials 3 Years after Administration of a Single Dose of Etranacogene Dezaparvovec (ASH 2023) - P2, P3 | "Concerns about increased hepatotoxicity of liver-directed adeno-associated viral (AAV) vectors in patients receiving potentially hepatotoxic HIV medications (eg, efavirenz) have excluded this population from participating in many of gene therapy hemophilia trials. Etranacogene dezaparvovec were observed to be safe and effective in a subset of study participants living with HIV. These results support the use of etranacogene dezaparvovec, the first approved liver-directed AAV-based gene therapy product for the treatment of patients with severe or moderately severe hemophilia B in the US and Europe, for eligible patients with controlled comorbid HIV infection. Owing to the small number of patients with HIV being enrolled in trials, long-term collection of data and special attention in the real-world setting is recommended."

Clinical • Gene therapy • P2b data • P3 data • Gene Therapies • Hematological Disorders • Hemophilia • Hemophilia B • Hepatitis C • Hepatology • Human Immunodeficiency Virus • Infectious Disease • Inflammation • Rare Diseases • CD4

Development of an Agent-Based Model to Investigate Response Durability in Hemophilia B Patients Treated with the AAV-Based Coagulation Factor IX (FIX) Gene Therapy Etranacogene Dezaparvovec (ASH 2024) - P3 | "This work demonstrates that ABMs can be used to predict how biological variables such as target cell turnover, liver physiology and viability along with product characteristics may impact response durability. While the model is applied herein to the context of AAV gene therapy-based FIX for hemophilia B, the computational framework should be adaptable to many other AAV-based gene therapies and diseases."

Clinical • Gene therapy • Gene Therapies • Hematological Disorders • Hemophilia • Hemophilia B • Rare Diseases

Improved Joint Health in the Phase 3 HOPE-B Trial of Etranacogene Dezaparvovec Gene Therapy for Hemophilia B over 36 Months of Follow up (ASH 2024) - "Conclusions : A single infusion of etranacogene dezaparvovec resulted in a discontinuation of continuous FIX concentrate prophylaxis, a reduction of (treated) joint ABR, which was significantly related to the steady state FIX level, and improved HJHS, with a positive effect on TJ resolution and prevention. The etranacogene dezaparvovec trial population, despite highly prevalent baseline hemophilic joint damage, demonstrated stable or improved joint health over 36 months of sustained endogenous FIX Padua expression."

Gene therapy • P3 data • Gene Therapies • Hematological Disorders • Hemophilia • Hemophilia B • Musculoskeletal Pain • Orthopedics • Pain • Rare Diseases • Rheumatology

Stable Factor IX Expression and Sustained Reductions in Factor IX Use 8 Years after Gene Therapy with CSL220 (Formerly AMT-060) in Adults with Hemophilia B (ASH 2024) - P, P1/2 | "Conclusions : Durability of factor expression is a key consideration in the decision-making process about gene therapy for patients and physicians. With just one amino acid difference in the expressed FIX protein, CSL220 is the precursor of etranacogene dezaparvovec (CSL222), which was the first gene therapy approved for the treatment of hemophilia B. This 8-year follow-up after CSL220 administration provides continued evidence for the durability, stability, and safety of FIX expression after AAV5-based gene therapy for the treatment of hemophilia B."

Clinical • Gene therapy • Gene Therapies • Hematological Disorders • Hemophilia • Hemophilia B • Rare Diseases

Scoping the Future: Using NICE Scopes to Inform PICO Prediction for EU Joint Clinical Assessment (ISPOR-EU 2025) - "The JCA PICO scoping pilot for etranacogene dezaparvovec gave 7 distinct PICOs, while the corresponding NICE scope included 1 PICO... NICE's consistently published PICO-based scoping documents can be used alongside other sources to support JCA PICO prediction, despite not being part of JCA. However, to accurately predict JCA PICO scopes and prepare for all necessary comparisons, HTDs must anticipate components of standard of care in each market, which may be grouped as a single comparator in NICE scoping documents. A transparent JCA scoping process with opportunity for HTD and other stakeholder inputs could help to reduce uncertainty in preparation for JCA."

Clinical

Lessons Learnt From PICO Exercise Developed by the Joint Clinical Assessment Subgroup for Etranacogene Dezaparvovec (ISPOR-EU 2025) - "The published etranacogene dezaparvovec PICO exercise included 7 PICOs, with the number increasing to over 20 comparisons when considering requested stratification. This represents a huge workload for HTDs and creates challenges for novel drug market entries. Furthermore, PICOs should be anticipated early to conduct systematic literature reviews and indirect treatment comparisons effectively, as evidence submission is expected within 100 days after the scoping process finalization."

Clinical • Gene Therapies • Hematological Disorders • Hemophilia • Hemophilia B • Rare Diseases

Evaluating High-Cost Gene Therapies for Noncancer Conditions: Insights From NICE's Standard Appraisal Process (ISPOR-EU 2025) - "We assessed the factors considered and whether the Innovative Medicines Fund (IMF) was employed to enable NICE's recommendations for high-cost, non-cancer therapies not meeting the criteria for HST. NICE STA guidance on gene therapies for non-cancer conditions as of June 2025 was reviewed. Three STAs were identified: Casgevy for severe sickle cell disease (TA1044), Casgevy for transfusion-dependent beta-thalassaemia (TA1003), and Hemgenix for moderately severe or severe haemophilia B (TA989). High-cost gene therapies can be recommended by NICE via standard STA under managed access if there is plausible cost-effectiveness potential and new evidence could feasibly be collected to address enough uncertainties."

Gene therapy • Beta-Thalassemia • Gene Therapies • Genetic Disorders • Hemophilia • Hemophilia B • Oncology • Rare Diseases • Sickle Cell Disease

Accelerating Therapeutic Innovation: Early Results From France's Accès Direct Scheme (ISPOR-EU 2025) - "Comparators were those defined by HAS. Five medicines entered the scheme: delgocitinib, danicopan, ruxolitinib, recombinant adjuvanted herpes zoster vaccine, and etranacogene dezaparvovec...At the time of analysis, two medicines remained within the program (<179 days).Price analyses showed coherent costs: €163.24 for herpes zoster vaccine and €70.00 for 100g of ruxolitinib cream (vs. €90.00 and no HAS-identified comparators respectively). The small number of medicines included and initial rejection of etranacogene dezaparpovec may reflect selection bias favoring suitable candidates... The small number of medicines included and initial rejection of etranacogene dezaparpovec may reflect selection bias favoring suitable candidates. However, preliminary findings suggest that "Accès Direct" effectively reduces time to reimbursement and improves patient access. While the scheme allows earlier funding, pricing remains similar or higher than comparators."

Dermatology • Gene Therapies • Herpes Zoster • Infectious Disease • Rare Diseases • Varicella Zoster

Design of experiments in rAAV manufacturing: Optimization of plasmid ratio for better upstream yield (ESGCT 2024) - "Since the FDA approval of Luxturna in 2017, six more AAV-based therapies have entered the global market including Beqvez™ for the treatment of haemophilia B. The one-time treatment for severe haemophilia B either with Hemgenix® or Beqvez™ has a price tag in the US of $3.5 million per dose. An increase of up to 3x more vector genome titres across four common serotypes and two transgenes of different lengths was found, with productivity for some serotypes at >7E+14 VG/L of clarified cell culture. The method can be applied at the pre-discovery stage to identify capsids and transgenes with better productivity, or later during the preclinical stage to fine tune the plasmid amount for better empty:full ratios."

Hematological Disorders • Hemophilia • Hemophilia B • Rare Diseases

Stable factor IX expression and sustained reductions in factor IX use 7 years after gene therapy with AMT-060 in adults with haemophilia B (ESGCT 2024) - P | "AMT-060 has an identical vector sequence to etranacogene dezaparvovec, without the activity-enhancing two nucleotide change in the human FIX coding sequence of the Padua FIX variant...Durability of factor expression is a key consideration in the decision-making process for patients and physicians. This 7-year follow-up after AMT-060 administration confirms the safety, durability and stability of FIX expression after AAV-based gene therapy reported previously."

Clinical • Gene therapy • Gene Therapies • Hematological Disorders • Hemophilia • Hemophilia A • Hemophilia B • Rare Diseases

Improving rAAV production: key adenoviral elements and their impact on vector yield and quality (ESGCT 2024) - "Recombinant Adeno-associated viruses (AAVs) are one of the most used viral vectors for gene therapy, with several products already on the market (e.g., Hemgenix, Roctavian, Elevidys). A smaller plasmid, without adenoviral structural proteins was generated, allowing a similar or better rAAV production across all tested serotypes. The knowledge generated from this study will ultimately facilitate the development of improved strategies for the large-scale production of high-titer and high-quality rAAV vectors, thereby advancing the gene therapy field."

Gene Therapies