Roctavian (valoctocogene roxaparvovec-rvox) / BioMarin - LARVOL DELTA

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

The deLIVERed promises of gene therapy: past, present and future of liver-directed gene therapy. (PubMed, Mol Ther) - "Adeno-associated virus (AAV) vectors have become the cornerstone of liver-directed therapies, demonstrating remarkable success in conditions such as hemophilia A and B, with FDA approved therapies like Etranacogene Dezaparvovec, Beqvez, and Roctavian marking milestones in the field. The advent of various genome-editing tools to repair genomic mutations or insert therapeutic DNAs into precise locations in the genome further enhances the potential for a single-dose medicine that will offer durable life-long therapeutic treatments. As advancements accelerate, liver-targeted gene therapy is poised to continue to transform the treatment landscape for both genetic and acquired disorders, for which unmet challenges remain."

Journal • Review • Gene Therapies • Hematological Disorders • Hemophilia • Hemophilia A • Hemophilia B • Hepatology • Immune Modulation • Immunology • Rare Diseases

GENEr8-1: Single-Arm Study To Evaluate The Efficacy and Safety of Valoctocogene Roxaparvovec in Hemophilia A Patients (BMN 270-301) (clinicaltrials.gov) - P3 | N=144 | Completed | Sponsor: BioMarin Pharmaceutical | Active, not recruiting ➔ Completed

Trial completion • Gene Therapies • Hematological Disorders • Hemophilia • Hemophilia A • Rare Diseases

A plain language summary on indirectly comparing bleeding after valoctocogene roxaparvovec gene therapy to bleeding with emicizumab prophylaxis. (PubMed, Expert Rev Hematol) - No abstract available

Journal • Gene Therapies

Corticosteroid use to mitigate transaminitis-associated decline in FVIII levels following valoctocogene roxaparvovec gene therapy: clinical practice guidance. (PubMed, J Thromb Haemost) - "An essential step in optimizing outcomes for patients who receive valoctocogene roxaparvovec is to review the extensive evidence currently available on this topic to determine practices for managing transaminitis, if it occurs. This forum article provides practical guidance based on the available clinical data and expert opinion for evaluating and managing transaminitis with corticosteroids to mitigate potential declines in FVIII activity levels in adults with severe hemophilia A who have received valoctocogene roxaparvovec."

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

Valoctocogene roxaparvovec estimated long-term durability of treatment effect: An extrapolation of the most recent clinical data (EAHAD 2025) - No abstract available

Clinical data

Final analysis of the phase 1/2 trial of valoctocogene roxaparvovec for severe hemophilia A (EAHAD 2025) - No abstract available

P1/2 data • Hematological Disorders • Hemophilia • Hemophilia A • Rare Diseases

Safety and efficacy of valoctocogene roxaparvovec with prophylactic glucocorticoids: 1-year results from the phase 3b, single-arm, open-label GENEr8-3 study. (PubMed, J Thromb Haemost) - "Based on cross-trial comparisons, prophylactic glucocorticoids do not confer safety or efficacy benefits compared with reactive glucocorticoid regimens."

Journal • P3 data • Gene Therapies • Hematological Disorders • Hemophilia • Hemophilia A • Rare Diseases

Outcomes and management of invasive procedures in participants with hemophilia A post gene therapy: a post hoc analysis of the GENEr8-1 phase III trial. (PubMed, Ther Adv Hematol) - "Invasive procedures were safely performed in participants following treatment with valoctocogene roxaparvovec. The questionnaire responses from investigators generally suggest they used endogenous FVIII activity derived from valoctocogene roxaparvovec to inform clinical decisions in a manner comparable to exogenously administered FVIII, and more commonly prescribed supplementary FVIII concentrate in the peri-procedural period for participants with lower FVIII activity levels."

Gene therapy • Journal • P3 data • Retrospective data • Gene Therapies • Hematological Disorders • Hemophilia • Hemophilia A • Rare Diseases

Efficacy, safety, and quality of life 4 years after valoctocogene roxaparvovec gene transfer for severe hemophilia A in the phase 3 GENEr8-1 trial. (PubMed, Res Pract Thromb Haemost) - "Alanine aminotransferase elevation was the most common adverse event during year 4 (56/131 participants); none required immunosuppressants. Valoctocogene roxaparvovec provides persistent FVIII expression, hemostatic control, and health-related quality of life improvements with no new safety signals."

HEOR • Journal • P3 data • Gene Therapies • Hematological Disorders • Hemophilia • Hemophilia A • Rare Diseases

Valoctocogene Roxaparvovec Estimated Long-Term Durability of Treatment Effect: An Extrapolation of the Most Recent Clinical Data (ASH 2024) - "In the scenario where 270-201 data were also used for the extrapolation, median estimated durability is estimated to range from 13.2–20.4 years. Conclusions : This analysis demonstrates that the observed therapeutic benefit is expected to be sustained beyond the 7 years of follow-up in existing clinical trials, illustrating the full treatment benefit that valoctocogene roxaparvovec can bring to PwSHA."

Clinical data • Gene Therapies • Hematological Disorders • Hemophilia • Hemophilia A • Rare Diseases

Comparative EQ-5D Utilities for Valoctocogene Roxaparvovec Gene Therapy and Emicizumab in People With Severe Hemophilia A Using a Matching-Adjusted Indirect Comparison (ISPOR-EU 2024) - "This study demonstrates the importance of reweighting utility outcomes via MAIC. After accounting for differences in patient characteristics and incorporating linear programming assumptions , valoctocogene roxaparvovec appears to show a greater utility increase than emicizumab. These results can inform treatment-arm specific utilities in cost-effectiveness modelling, capturing utility gain beyond reductions in bleeds."

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

Finding a Way for Patients to Access Gene Therapies (ISPOR-EU 2024) - "Out of 9 funded single-administration GTx (eladocagene exuparvovec, etranacogene dezaparvovec, betibeglogene autotemcel, valoctocogene roxaparvovec, voretigene neparvovec, exagamglogene autotemcel, lovotibeglogene autotemcel, atidarsagene autotemcel, onasemnogene abeparvovec), RSAs were identified in the US (n=7), UK (n=5), Canada (n=3), and Australia (n=2)... To manage uncertainties around long-term benefits and financial impact, local decision-makers implement RSAs. Canada and UK mainly use financial-based schemes built on simple price discounts. Australia and the US aim at implementing schemes whereby treatment cost payers incur corresponds to expected health outcome for a particular patient."

Clinical • Gene therapy • Gene Therapies • Rare Diseases

Drivers of Access to Gene Therapies in Poland and Selected Central and Eastern Europe Countries (ISPOR-EU 2024) - " The review identified 11 HTA reports on 6 single-administration GTx (eladocagene exuparvovec, etranacogene dezaparvovec, valoctocogene roxaparvovec, voretigene neparvovec, atidarsagene autotemcel, onasemnogene abeparvovec)... The availability of GTx in selected CEE countries is limited. Considering there are 88 ongoing GTx phase 3 clinical trials, with 58 expected to be completed within the next 5 years, the decision-makers will likely face even greater challenges to balance patient access and impact on public budgets."

Gene therapy • Gene Therapies • Rare Diseases

Gene Therapy for Hemophilia. (PubMed, Blood Adv) - "Evolution Long-term clinical studies have provided insight into the efficacy, safety, and durability of AAV-mediated gene therapies for hemophilia A and B. Gene therapies have now been approved for hemophilia A (valoctocogene roxaparvovec) and hemophilia B (etranacogene dezaparvovec; fidanacogene elaparvovec) in select regions. Application The approved gene therapies are associated with a strong reduction in bleeding tendency and increased FVIII or FIX activity levels, without the need for additional FVIII or FIX replacement therapies, in the vast majority of patients. Future Steps Improvements in AAV technology, protein expression, and immunogenicity may render AAV-mediated gene therapies more efficient, longer lasting and safer for people with hemophilia A or B."

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

Biological Barriers for Drug Delivery and Development of Innovative Therapeutic Approaches in HIV, Pancreatic Cancer, and Hemophilia A/B. (PubMed, Pharmaceutics) - "In 2018, the FDA approval of patisiran paved the way for small interfering RNAs (siRNAs) to become a novel class of nucleic-acid-based therapeutics, which-upon effective drug delivery to their target cells-allow to elegantly regulate the post-transcriptional gene expression. The recent approvals of valoctocogene roxaparvovec and etranacogene dezaparvovec for the treatment of hemophilia A and B, respectively, mark the breakthrough of viral-vector-based gene therapy as a new tool to cure disease...Our second goal is to showcase which therapeutic approaches designed to cross disease-specific biological barriers have been promising in effectively treating disease. In this context, we will exemplify how the right selection of the drug category and delivery vehicle, mode of administration, and therapeutic target(s) can help overcome various biological barriers to prevent, treat, and cure disease."

Journal • Review • Gastrointestinal Cancer • Gastrointestinal Disorder • Gene Therapies • Genetic Disorders • Hematological Disorders • Hemophilia • Hemophilia A • Hemophilia B • Hepatology • Human Immunodeficiency Virus • Infectious Disease • Oncology • Pancreatic Cancer • Pancreatitis • Rare Diseases • Solid Tumor

A systematic review of cost-effectiveness analyses of gene therapy for hemophilia type A and B. (PubMed, J Manag Care Spec Pharm) - "In 2022-2023, the US Food and Drug Administration approved 2 novel gene therapies, valoctocogene roxaparvovec and etranacogene dezaparavovec, for hemophilia A and B, respectively...Despite the high upfront costs of the gene therapies, all included studies' (3 hemophilia A and 1 hemophilia B) modeled results showed that gene therapies had lower overall costs and better health outcomes compared with factor concentrate replacement therapies and emicizumab...The novel hemophilia gene therapy treatments can potentially be a cost-effective use of treatment resources if the treatment effects are durable over time. To reduce the risk for payers while still facilitating patient access, outcomes-based agreements similar to what has recently been proposed by the Centers for Medicare & Medicaid Services for sickle-cell therapies are well supported."

Cost effectiveness • Gene therapy • HEOR • Journal • Review • Gene Therapies • Hematological Disorders • Hemophilia • Hemophilia A • Hemophilia B • Rare Diseases

Gene Therapy Study in Severe Hemophilia a Patients with Antibodies Against AAV5 (clinicaltrials.gov) - P1/2 | N=3 | Terminated | Sponsor: BioMarin Pharmaceutical | Active, not recruiting ➔ Terminated; Early rollover into long-term extension study

Gene therapy • Trial termination • Gene Therapies • Hematological Disorders • Hemophilia • Hemophilia A • Rare Diseases

Liver-related aspects of valoctocogene roxaparvovec gene therapy for hemophilia A: expert guidance for clinical practice. (PubMed, Blood Adv) - "Patients with ALT elevation should receive prednisone 60 mg/day for 2 weeks, followed by stepwise tapering when ALT returns to baseline. ALT monitoring should continue long-term (every 3-6 months), along with abdominal ultrasound (every 6 months) and TE (yearly) evaluations. When patients with good liver health are selected for treatment and closely monitored thereafter, ALT elevations can be promptly treated and are expected to resolve without long-term hepatic sequelae."

Gene therapy • Journal • Autoimmune Hepatitis • Fibrosis • Gene Therapies • Hematological Disorders • Hemophilia • Hepatology • Immunology • Infectious Disease • Inflammation • Rare Diseases

Marketing authorisation for rare diseases: The European regulatory perspective using the example of gene and cell therapies (PubMed, Z Evid Fortbild Qual Gesundhwes) - "Two out of fifteen gene therapies that have been approved in the European Union since 2018 are used as case studies: Libmeldy (atidarsagen autotemcel) for the treatment of patients with metachromatic leukodystrophy, and Roctavian (valoctocogen roxaparvovec) for the treatment of patients with haemophilia A. Special aspects of the evaluation of single-arm trials with small sample size and requirements with regard to the isolation and causal attribution of the treatment effect are discussed. The role of clinical data obtained under everyday conditions (real world data) to support the generation of evidence in the pre- and post authorisation phase is critically examined. Furthermore, the paper outlines aspects related to conditional versus standard marketing authorisations as well as aspects related to registry-based non-interventional studies in the context of market and patient access to urgently needed drugs."

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

Transitioning patients with severe haemophilia A from emicizumab prophylaxis to valoctocogene roxaparvovec gene therapy: Real-world clinical experience. (PubMed, Haemophilia) - No abstract available

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

The longitudinal kinetics of AAV5 vector integration profiles and evaluation of clonal expansion in mice. (PubMed, Mol Ther Methods Clin Dev) - "A mouse model was used to investigate integration profiles of an AAV serotype 5 (AAV5) vector produced using Sf and HEK293 cells that mimic key features of valoctocogene roxaparvovec (AAV5-hFVIII-SQ), a gene therapy for severe hemophilia A. The majority (95%) of vector genome reads were derived from episomes, and mean (± standard deviation) integration frequency was 2.70 ± 1.26 and 1.79 ± 0.86 integrations per 1,000 cells for Sf- and HEK293-produced vector...Integrations were enriched near transcription start sites of genes highly expressed in the liver (p = 1 × 10-4) and less enriched for genes of lower expression. We found no evidence of tumorigenesis or fibrosis caused by the vector integrations."

Journal • Preclinical • Fibrosis • Gene Therapies • Hematological Disorders • Hemophilia • Immunology • Oncology • Rare Diseases

Gene Therapy Study in Severe Haemophilia A Patients (270-201) (clinicaltrials.gov) - P1/2 | N=15 | Completed | Sponsor: BioMarin Pharmaceutical | Active, not recruiting ➔ Completed

Gene therapy • Trial completion • Gene Therapies • Hematological Disorders • Hemophilia • Rare Diseases

Blood biodistribution and vector shedding of valoctocogene roxaparvovec in people with severe hemophilia A. (PubMed, Blood Adv) - P3 | "The replication-incompetent nature of valoctocogene roxaparvovec, coupled with the steady clearance of total and encapsidated vector DNA from shedding matrices, indicates risk of transmission is low. This trial is registered at www.clinicaltrials.gov as NCT03370913."

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

Roctavian Gene Therapy for Hemophilia A. (PubMed, Blood Adv) - "This observation has been qualitatively replicated in animal models. The development and approval of Roctavian is a landmark in HA therapeutics, though next-generation approaches are needed before HA gene therapy fulfills its promise of stable FVIII expression that normalizes hemostasis."

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