Gene Therapy for Hemophilia A

(GENEr8-INH Trial)

Not currently recruiting at 20 trial locations

Overseen By Trial Specialist

Age: 18+

Sex: Male

Trial Phase: Phase 1 & 2

Sponsor: BioMarin Pharmaceutical

Must not be taking: Immune tolerance therapy

Disqualifiers: Active infection, Immunosuppressive disorder, Renal dysfunction, Liver dysfunction, others

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

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, valoctocogene roxaparvovec, to determine its safety and effectiveness for individuals with severe hemophilia A who have experienced FVIII inhibitors. The trial consists of two parts: one for those currently with these inhibitors and another for those who had them in the past. Suitable candidates have lived with hemophilia A, have had FVIII inhibitors, and have received hemophilia treatment in the past year. As a Phase 1/Phase 2 trial, the research aims to understand how the treatment works in people and measure its effectiveness in an initial, smaller group, offering participants a chance to be among the first to benefit from this innovative therapy.

Will I have to stop taking my current medications?

The trial does not specify if you need to stop taking your current medications. However, if you are currently undergoing immune tolerance induction therapy or prophylaxis with FVIII, you cannot participate in Part A of the study.

Is there any evidence suggesting that valoctocogene roxaparvovec is likely to be safe for humans?

Research has shown that valoctocogene roxaparvovec, a gene therapy for hemophilia A, is generally safe. Studies have found that this treatment can effectively reduce bleeding episodes. In a large study that tracked participants for up to five years, 81.3% of people maintained control over their bleeding.

Over two years, the treatment continued to work well by maintaining levels of factor VIII, a protein important for blood clotting, which helped reduce bleeding. Most participants experienced positive results without major safety concerns. Although a few people returned to their previous treatments, this was uncommon.

Overall, valoctocogene roxaparvovec appears well-tolerated, with safety data supporting its use in people with hemophilia A. However, like any treatment, it may have some risks, so discussing it with a doctor is important. ^{1 2 3 4 5}

Why do researchers think this study treatment might be promising?

Researchers are excited about Valoctocogene Roxaparvovec because it offers a novel approach to treating Hemophilia A through gene therapy. Unlike traditional treatments, which typically require regular intravenous infusions of clotting factors, this therapy involves a single administration that aims to provide long-term relief. Valoctocogene Roxaparvovec works by delivering a functional copy of the gene responsible for producing clotting factor VIII, potentially reducing or even eliminating the need for frequent treatments. This could significantly improve the quality of life for patients by minimizing the burden of ongoing therapy.

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

Research has shown that valoctocogene roxaparvovec, the treatment under study in this trial, could be a promising option for severe hemophilia A. In one study, 81.3% of participants experienced a lasting increase in Factor VIII, a protein crucial for stopping bleeding. Another study found that this gene therapy reduced bleeding and maintained stable Factor VIII levels for at least two years. Four years after treatment, the average Factor VIII level was 34%, indicating long-term benefits. These results suggest that valoctocogene roxaparvovec could significantly improve outcomes for people with severe hemophilia A. ^{1 2 3 6 7}

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 had inhibitors to Factor VIII. They must not drink alcohol for a year post-treatment, use effective contraception, and cannot have other bleeding disorders or significant organ dysfunction. Part A includes those currently with inhibitors; Part B is for those with a past history of inhibitors.

Inclusion Criteria

Part A: Demonstrated no immunological tolerance to exogenous FVIII. Part B: Demonstrated tolerance to exogenous FVIII and negative FVIII inhibitor screening titer < 0.6 BU.

I have been on hemophilia treatment in the past year.

Sexually active participants must agree to use an acceptable method of effective contraception. Participants must agree to contraception use for at least 12 weeks post-infusion.

Exclusion Criteria

Detectable pre-existing antibodies to the AAV5 capsid.

I have a bleeding disorder that is not hemophilia A.

I am receiving or plan to receive immune therapy for FVIII during the study.

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

1 day

1 visit (in-person)

Follow-up

Participants are monitored for safety and effectiveness after treatment

60 months

What Are the Treatments Tested in This Trial?

Interventions

• Valoctocogene Roxaparvovec

Trial Overview The study tests the safety and effectiveness of Valoctocogene Roxaparvovec in two groups: one with active Factor VIII inhibitors (Part A) and another that previously had these inhibitors but now tolerates FVIII (Part B).

How Is the Trial Designed?

Group I: Valoctocogene roxaparvovec Open Label Experimental Treatment 1 Intervention

Single administration of valoctocogene roxaparvovec at a dose of 6E13 vg/kg in Active Inhibitor Population (Part A) and Prior Inhibitor Population (Part B).

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 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]

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]

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]

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]

Citations

1. 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 ... Data from longest and largest hemophilia gene therapy study demonstrates sustained factor VIII expression and bleed control, with 81.3% of individuals ...

2. 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 ...

3. pubmed.ncbi.nlm.nih.gov pubmed.ncbi.nlm.nih.gov/39800255/

1-year results from the phase 3b, single-arm, open-label ... ... efficacy of valoctocogene roxaparvovec ... Results: Overall, 22 participants with severe hemophilia A received valoctocogene roxaparvovec.

4. 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 ...

5. 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%.

6. pubmed.ncbi.nlm.nih.gov pubmed.ncbi.nlm.nih.gov/36812433/

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 ...

7. sciencedirect.com sciencedirect.com/science/article/pii/S1538783625000029

Safety and efficacy of valoctocogene roxaparvovec with ... Based on cross-trial comparisons, prophylactic glucocorticoids do not confer safety or efficacy benefits compared with reactive glucocorticoid regimens.