First Data from the Phase 3 HOPE-B Gene Therapy Trial: Efficacy and Safety of Etranacogene Dezaparvovec (AAV5-Padua hFIX variant; AMT-061) in Adults with Severe or Moderate-Severe Hemophilia B Treated Irrespective of Pre-Existing Anti-Capsid Neutralizing Antibodies

Pipe, Steven W.; Recht, Michael; Key, Nigel S.; Leebeek, Frank W.G.; Castaman, Giancarlo; Lattimore, Susan; Valk, Paul van der; Peerlinck, Kathelijne; Coppens, Michiel; O’Connell, Niamh M; Pasi, John; Kampmann, Peter; Meijer, Karina; Drygalski, Annette von; Hermans, Cédric; Astermark, Jan; Klamroth, Robert; Lemons, Richard S.; Visweshwar, Nathan; Crary, Shelley E.; Kazmi, Rashid; Symington, Emily; Escobar, Miguel A.; Gomez, Esteban; Kruse‐Jarres, Rebecca; Kotowski, Adam; Quon, Doris; Wang, Michael; Wheeler, Allison P.; Verweij, Stephanie; Colletta, V; Bajma, Naghmana; Gut, Robert; Miesbach, Wolfgang

doi:10.1182/blood-2020-143560

Cited by 15 publications

(20 citation statements)

References 0 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…3 A trial using Spark100 (Table 3), a modified rAAV variant, at a fixed dose of 5 × 10 11 vg/kg, resulted in 22.9% physiologic FIX expression at showed that 37.2% of participants had steady FIX expression 6 months after vector administration. 42 Importantly, no relationship between corticosteroid treatment for elevated transaminases and FIX expression level or immunity was observed 42,92 (Figure 3).…”

Section: Clinical Development Of Raav Vectormediated Fix Gene Therapymentioning

confidence: 94%

The intersection of vector biology, gene therapy, and hemophilia

Lisowski

Staber

Wright

et al. 2021

Research and Practice in Thrombosis and Haemostasis

View full text Add to dashboard Cite

show abstract

Section: Clinical Development Of Raav Vectormediated Fix Gene Therapymentioning

confidence: 94%

The intersection of vector biology, gene therapy, and hemophilia

Lisowski

Staber

Wright

et al. 2021

Research and Practice in Thrombosis and Haemostasis

View full text Add to dashboard Cite

show abstract

“…As anticipated, the substitution of the FIX Padua variant has mediated FIX activity that is sustained and that exceeds the activity achieved by the identical doses of the vector expressing WT FIX. From the standpoint of immunology, however, the novel aspect is that subjects who were determined to have pre-existing AAV5 neutralizing antibodies, as measured by the sponsor's assay methods, were not excluded from participation (see Section 3.1); the sponsor's preliminary report is provocative in that all subjects with preexisting AAV5 NAb of low or intermediate titer (up to a titer of >600 using the sponsor's assay) sustained FIX activity past week 26 (follow-up ongoing) with only one subject with a higher titer NAb failing to show FIX correction [34].…”

Section: Figurementioning

confidence: 99%

“…Although the presence of anti-AAV antibodies is expected to limit the efficacy of gene transfer, hemophilia trials have shown no evidence of toxicities associated with the presence of preexisting humoral immunity to the vector [12]. An ongoing Phase 3 AAV gene transfer trial in patients with hemophilia B did not observe a clear relationship between the emergence of treatment-related adverse events and the presence of detectable NAbs at baseline [34]. Conversely, trials in which large vector doses have been administered (e.g., >1 × 10 14 vg/kg in trials of gene transfer for DMD [86]) have documented activation of complement, which may be mediated by antibody binding to a pathogen.…”

Section: Adaptive Immunitymentioning

confidence: 99%

Emerging Immunogenicity and Genotoxicity Considerations of Adeno-Associated Virus Vector Gene Therapy for Hemophilia

Monahan

Négrier

Tarantino

et al. 2021

JCM

View full text Add to dashboard Cite

Adeno-associated viral (AAV) vector gene therapy has shown promise as a possible cure for hemophilia. However, immune responses directed against AAV vectors remain a hurdle to the broader use of this gene transfer platform. Both innate and adaptive immune responses can affect the safety and efficacy of AAV vector–mediated gene transfer in humans. These immune responses may be triggered by the viral capsid, the vector’s nucleic acid payload, or other vector contaminants or excipients, or by the transgene product encoded by the vector itself. Various preclinical and clinical strategies have been explored to overcome the issues of AAV vector immunogenicity and transgene-related immune responses. Although results of these strategies are encouraging, more efficient approaches are needed to deliver safe, predictable, and durable outcomes for people with hemophilia. In addition to durability, long-term follow-up of gene therapy trial participants will allow us to address potential safety concerns related to vector integration. Herein, we describe the challenges with current methodologies to deliver optimal outcomes for people with hemophilia who choose to undergo AAV vector gene therapy and the potential opportunities to improve on the results.

show abstract

“…Etranacogene dezaparvovec phase 2b and HOPE-B phase 3 clinical trials. 32,34,35,37,38 . Oncogenesis concerns: evaluation of a case of hepatocellular carcinoma in HOPE-B Of significance, HOPE-B was placed on clinical hold in December 2021 to investigate the diagnosis of hepatocellular carcinoma (HCC) in a 69-year-old White, non-Hispanic male with moderately severe hemophilia B.…”

Section: Infusion-related Reactions In Hope-bmentioning

confidence: 99%

Etranacogene dezaparvovec for hemophilia B gene therapy

Thornburg

2021

Therapeutic Advances in Rare Disease

View full text Add to dashboard Cite

The treatment landscape for hemophilia has been rapidly changing with introduction of novel therapies. Gene therapy for hemophilia is a promising therapeutic option for sustained endogenous factor production to mitigate the need for prophylactic treatment to prevent spontaneous and traumatic bleeding. Etranacogene dezaparvovec is an investigational factor IX (FIX) gene transfer product that utilizes the adeno-associated virus (AAV) 5 vector with a liver-specific promoter and a hyperactive FIX transgene. Here, the development of etranacogene dezaparvovec and available efficacy and safety data from clinical trials are reviewed. Overall, etranacogene dezaparvovec provides sustained FIX expression for more than 2 years and allows for a bleed and infusion-free life in the majority of patients. Safety, efficacy, and quality-of-life data will inform shared decision-making for patients who are considering gene therapy. Long-term follow-up regarding duration of expression and safety are crucial. Plain Language Summary Factor IX Padua gene therapy to boost clotting factor and prevent bleeding for people living with hemophilia B People living with hemophilia have low or missing clotting factor, which can lead to bleeding that is unexpected or caused by a traumatic event (such as a sports injury or surgery). There are two main types of hemophilia: clotting factor (F)VIII deficiency (known as hemophilia A) and FIX deficiency (known as hemophilia B). People living with the severe or moderately severe forms of hemophilia (clotting factor levels below 3% of normal) need regular treatment, typically by infusions into the vein, to stop or prevent bleeding and damage to their joints. Gene therapy is currently being investigated as a new treatment option that introduces a working copy of the clotting factor gene to the liver. Following treatment, clotting factor is produced by the liver. Etranacogene dezaparvovec [Et-ra-na-co-gene dez-a-par-vo-vec] is a form of gene therapy for people living with hemophilia B. This form of gene therapy includes a modified form of FIX (FIX Padua) which produces high levels of FIX activity compared with normal FIX. It is being tested to see whether individuals will have low rates of bleeding and not need to treat themselves with clotting factor. In the clinical trials, participants with FIX levels below 2% (of normal) receive a single gene therapy infusion. The results of the trials have so far shown that patients given etranacogene dezaparvovec have continuous production of FIX, whereby they have reported much less bleeding and factor treatment. Questions relating to the safety of the gene therapy and how long it works will hopefully be answered through long-term follow-up of the patients once the trials are completed.

show abstract

First Data from the Phase 3 HOPE-B Gene Therapy Trial: Efficacy and Safety of Etranacogene Dezaparvovec (AAV5-Padua hFIX variant; AMT-061) in Adults with Severe or Moderate-Severe Hemophilia B Treated Irrespective of Pre-Existing Anti-Capsid Neutralizing Antibodies

Cited by 15 publications

References 0 publications

The intersection of vector biology, gene therapy, and hemophilia

The intersection of vector biology, gene therapy, and hemophilia

Emerging Immunogenicity and Genotoxicity Considerations of Adeno-Associated Virus Vector Gene Therapy for Hemophilia

Etranacogene dezaparvovec for hemophilia B gene therapy

Contact Info

Product

Resources

About