Gene Therapy for Hemophilia A

(GENEr8-3 Trial)

No longer recruiting at 12 trial locations

Overseen By Trial Specialist

Age: 18+

Sex: Male

Trial Phase: Phase 3

Sponsor: BioMarin Pharmaceutical

Must be taking: Prophylactic corticosteroids

Must not be taking: Systemic immunosuppressants

Disqualifiers: Liver disease, Hepatitis B, Hepatitis C, others

No Placebo Group All trial participants will receive the active study treatment (no placebo)

Pivotal Trial (Near Approval) This treatment is in the last trial phase before FDA approval

Prior Safety Data This treatment has passed at least one previous human trial

Compensation: Varies

Number of Visits: 1

Duration: 1 day

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial tests a new gene therapy treatment called valoctocogene roxaparvovec for individuals with severe hemophilia A, a condition where blood doesn't clot well. Researchers aim to determine if this treatment, combined with corticosteroids (medications that reduce inflammation), is safe and effective. It targets males who have managed hemophilia A with preventive treatments for over a year. Participants should have a history of frequent bleeding episodes and no previous issues with certain blood inhibitors. As a Phase 3 trial, this study represents the final step before FDA approval, offering participants a chance to contribute to a potentially groundbreaking treatment.

Will I have to stop taking my current medications?

The trial protocol does not specify if you need to stop taking your current medications. However, you must not use systemic immunosuppressive agents, except corticosteroids, within 30 days before the infusion.

Is there any evidence suggesting that this treatment is likely to be safe for humans?

Research has shown that valoctocogene roxaparvovec has been tested for several years. In these studies, individuals with severe hemophilia A experienced fewer bleeding issues and improved blood clotting due to increased Factor VIII, a key protein for clotting. The treatment's safety has been monitored over several years, and five-year data suggest it is generally well-tolerated.

Some individuals experienced mild to moderate side effects, which can be managed. For instance, some had increased liver enzymes, treated with medical care. Overall, the treatment appears safe based on the available clinical data. ^{1 2 3 4 5}

Why do researchers think this study treatment might be promising?

Valoctocogene roxaparvovec is unique because it uses gene therapy to potentially offer a long-lasting solution for Hemophilia A. Unlike traditional treatments that require regular infusions of clotting factors, this therapy involves a one-time administration that targets the root cause by delivering a working copy of the gene responsible for producing Factor VIII, a crucial blood-clotting protein. Researchers are excited because this approach could significantly reduce or even eliminate the need for frequent injections, offering a more convenient and effective treatment option.

What evidence suggests that valoctocogene roxaparvovec might be an effective treatment for hemophilia A?

Research has shown that valoctocogene roxaparvovec, the investigational treatment in this trial, can help treat severe hemophilia A. This gene therapy enables the body to produce factor VIII, a protein crucial for blood clotting that individuals with this condition lack. Over several years, recipients of this treatment experienced fewer bleeding episodes and reported improved overall health. The treatment's safety has remained consistent over time. These findings suggest that valoctocogene roxaparvovec could offer significant benefits for those with severe hemophilia A. ^{1 6 7 8 9}

Who Is on the Research Team?

Medical Monitor, MD

Principal Investigator

BioMarin Pharmaceutical

Are You a Good Fit for This Trial?

This trial is for adult males with severe hemophilia A, who have been on prophylactic therapy for at least a year and have had significant exposure to FVIII treatments. They must not have any history of inhibitors to FVIII and agree to use contraception post-infusion. Those with antibodies against the treatment vector, active infections, immune disorders, or unrelated bleeding disorders cannot participate.

Inclusion Criteria

I have been on preventive treatment for hemophilia for at least a year.

I have been treated with FVIII or cryoprecipitate for at least 150 days.

No previous documented history of a detectable FVIII inhibitor, <0.6 Bethesda Units (BU)

Exclusion Criteria

I do not have severe kidney, liver problems, infections, or a history of liver cancer.

I have a bleeding disorder that is not hemophilia A.

I have low levels of antibodies against AAV5, if any.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Single administration of valoctocogene roxaparvovec at a dose of 6E13 vg/kg with prophylactic corticosteroids

1 day

1 visit (in-person)

Efficacy Evaluation Period (EEP)

Monitoring of participants for changes in bleeding episodes and FVIII activity post-treatment

From Week 5 to last visit

Follow-up

Participants are monitored for safety and effectiveness after treatment

52 weeks

What Are the Treatments Tested in This Trial?

Interventions

• Valoctocogene Roxaparvovec

Trial Overview The study tests valoctocogene roxaparvovec's effectiveness and safety in treating severe hemophilia A when used alongside preventive steroids. It aims to see if this gene therapy can reduce bleeding episodes by providing a functional copy of the faulty gene causing hemophilia.

How Is the Trial Designed?

Group I: valoctocogene roxaparvovec Experimental Treatment 1 Intervention

Single administration of valoctocogene roxaparvovec at a dose of 6E13 vg/kg with prophylactic corticosteroids

Who Is Running the Clinical Trial?

BioMarin Pharmaceutical

Lead Sponsor

Trials

162

Recruited

115,000+

Alexander Hardy

BioMarin Pharmaceutical

Chief Executive Officer since 2023

MBA from INSEAD

Greg Friberg

BioMarin Pharmaceutical

Chief Medical Officer

MD from New York Medical College

Published Research Related to This Trial

Gene therapies like Roctavian® and Hemgenix® have been approved for treating severe hemophilia A and B, respectively, showing significant increases in clotting factor levels and reductions in bleeding episodes based on phase III clinical trial data.

While most patients experienced short-term liver inflammation that was manageable with immune suppression, there remains variability in treatment response, and further research is needed to determine the long-term stability of factor expression and the potential for a permanent cure.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Hemophilia Gene Therapy: The End of the Beginning? De Wolf, D., Singh, K., Chuah, MK., et al.[2023]

Recent advancements in hemophilia treatment include monoclonal antibodies that mimic factor VIII activity, providing effective therapy for all hemophilia A phenotypes, including those with inhibitors, and improving patient quality of life with safer and longer-lasting effects.

Gene therapy, particularly using CRISPR/Cas technology, shows promise for potentially curing hemophilia by permanently editing genes, with ongoing developments aimed at minimizing risks and enhancing effectiveness.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Current Therapies in Hemophilia: From Plasma-Derived Factor Modalities to CRISPR/Cas Alternatives. Jair Lara-Navarro, I., Rebeca Jaloma-Cruz, A.[2022]

Gene therapy for hemophilia, specifically with products like valoctocogene roxaparvovec for hemophilia A and etranacogene dezaparvovec for hemophilia B, is nearing approval and represents a significant advancement in treatment, allowing for a one-time infusion that leads to the body's own production of missing clotting factors.

Clinical observations indicate that gene therapy can provide sustained benefits for over 5 years after a single treatment, with manageable side effects such as temporary increases in liver enzymes, suggesting a promising safety profile for these therapies.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Gene therapy for hemophilia. Nathwani, AC.[2023]

Valoctocogene roxaparvovec (Roctavian) and etranacogene dezaparavovec (Hemgenix) are effective gene therapies for hemophilia A and B, respectively, with phase 3 studies showing significant increases in clotting factor levels and reductions in bleeding events among participants (n=134 for Roctavian and n=54 for Hemgenix).

Both therapies were associated with manageable safety profiles, primarily involving elevated liver function tests, and they improved patients' quality of life by mimicking natural clotting factor production, offering a promising alternative to traditional replacement therapies.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Valoctocogene Roxaparvovec and Etranacogene Dezaparavovec: Novel Gene Therapies for Hemophilia A and B. Dougherty, JA., Dougherty, KM.[2023]

Citations

1. nejm.org nejm.org/doi/full/10.1056/NEJMoa2211075

Two-Year Outcomes of Valoctocogene Roxaparvovec ... The study data show the durability of factor VIII activity and bleeding reduction and the safety profile of valoctocogene roxaparvovec at least 2 years after ...

2. pubmed.ncbi.nlm.nih.gov pubmed.ncbi.nlm.nih.gov/35294811/

Valoctocogene Roxaparvovec Gene Therapy for ... Conclusions: In patients with severe hemophilia A, valoctocogene roxaparvovec treatment provided endogenous factor VIII production and ...

3. sciencedirect.com sciencedirect.com/science/article/pii/S1538783624001843

Three-year outcomes of valoctocogene roxaparvovec gene ... Valoctocogene roxaparvovec provides hemostatic efficacy with unchanged safety after 3 years. Outcomes will be assessed for up to 15 years after treatment.

4. biomarin.com biomarin.com/news/press-releases/biomarin-presents-new-phase-3-four-year-data-underscoring-long-term-safety-and-efficacy-of-roctavian-valoctocogene-roxaparvovec-rvox-at-international-society-on-thrombosis-and-haemostasis-202-3/

BioMarin Presents New Phase 3, Four-Year Data ... In an additional analysis from the Phase 3 GENEr8-1 study, ROCTAVIAN provided important improvements in health-related quality of life (HRQoL) over four years ...

5. nejm.org nejm.org/doi/full/10.1056/NEJMoa2113708

Valoctocogene Roxaparvovec Gene Therapy for ... In patients with severe hemophilia A, valoctocogene roxaparvovec treatment provided endogenous factor VIII production and significantly reduced ...

6. biomarin.com biomarin.com/news/press-releases/biomarin-presents-five-year-phase-3-results-reinforcing-long-term-efficacy-and-safety-of-roctavian-valoctocogene-roxaparvovec-rvox-at-international-society-on-thrombosis-and-haemostasis-2025-c/

BioMarin Presents Five-Year Phase 3 Results Reinforcing ... The analysis showed that people who received ROCTAVIAN in the Phase 3 GENEr8-1 study experienced improvements across all measures, including bleeding risk, ...

7. sciencedirect.com sciencedirect.com/science/article/pii/S2475037924003108

Original Article Efficacy, safety, and quality of life 4 years ... Here, we present data from all follow-ups and the fourth year of GENEr8-1 that show near-stable FVIII activity from the previous year and durable protection ...

8. roctavian.com roctavian.com/en-us/roctavian-results/

ROCTAVIAN® (valoctocogene roxaparvovec-rvox) Results ... ROCTAVIAN had the longest and largest Phase 3 clinical study in severe hemophilia A. 4 years after ROCTAVIAN, the average Factor VIII activity level was 34%.

9. pubmed.ncbi.nlm.nih.gov pubmed.ncbi.nlm.nih.gov/38614387/

Three-year outcomes of valoctocogene roxaparvovec gene ... Valoctocogene roxaparvovec transfers a human factor (F)VIII coding sequence into hepatocytes of people with severe hemophilia A to provide bleeding protection.