Gene Therapy for Hemophilia A

(GENEr8-3 Trial)

Recruiting at 11 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

22 Participants Needed

Trial Summary

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.

What data supports the effectiveness of the treatment Valoctocogene Roxaparvovec for Hemophilia A?

Valoctocogene Roxaparvovec has shown sustained clinical benefits in people with severe Hemophilia A, with significant increases in factor VIII levels and a reduction in bleeding episodes, as demonstrated in phase III clinical trials. It has been approved by the European Commission and FDA, indicating its effectiveness and safety for treating Hemophilia A. ^{1 2 3 4 5}

Is Valoctocogene Roxaparvovec safe for humans?

Valoctocogene Roxaparvovec, a gene therapy for severe hemophilia A, has been studied for safety in clinical trials. It has received conditional approval in the EU, indicating that it has been deemed safe enough for use in adults with specific conditions, although ongoing monitoring and further studies are likely required. ^{1 6 7 8 9}

How does the gene therapy treatment Valoctocogene Roxaparvovec for Hemophilia A differ from other treatments?

Valoctocogene Roxaparvovec is unique because it is a gene therapy designed to provide a long-term solution by delivering a functional copy of the gene responsible for producing the clotting factor missing in Hemophilia A, potentially reducing or eliminating the need for regular infusions of clotting factor concentrates. ^{10 11 12 13 14}

What is the purpose of this trial?

This trial tests a new gene therapy combined with anti-inflammatory medication for patients with severe hemophilia A. The treatment aims to help their bodies produce a necessary clotting protein and reduce inflammation.

Research Team

Medical Monitor, MD

Principal Investigator

BioMarin Pharmaceutical

Eligibility Criteria

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

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

Treatment Details

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.

Participant Groups

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

Findings from Research

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]

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]

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]

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]

References

1. England pubmed.ncbi.nlm.nih.gov

Persistence of haemostatic response following gene therapy with valoctocogene roxaparvovec in severe haemophilia A. [2022]

2. United States pubmed.ncbi.nlm.nih.gov

Hemophilia Gene Therapy: The End of the Beginning? [2023]

3. United States pubmed.ncbi.nlm.nih.gov

Gene therapy for hemophilia. [2023]

4. England pubmed.ncbi.nlm.nih.gov

Hemophilia gene therapy: first, do no harm. [2023]

5. Japan pubmed.ncbi.nlm.nih.gov

Current Therapies in Hemophilia: From Plasma-Derived Factor Modalities to CRISPR/Cas Alternatives. [2022]

6. New Zealand pubmed.ncbi.nlm.nih.gov

Valoctocogene Roxaparvovec: First Approval. [2022]

7. United States pubmed.ncbi.nlm.nih.gov

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

8. England pubmed.ncbi.nlm.nih.gov

Matching-adjusted indirect comparison of bleeding outcomes in severe haemophilia A: Comparing valoctocogene roxaparvovec gene therapy, emicizumab prophylaxis, and FVIII replacement prophylaxis. [2023]

9. United States pubmed.ncbi.nlm.nih.gov

Two-Year Outcomes of Valoctocogene Roxaparvovec Therapy for Hemophilia A. [2023]

10. England pubmed.ncbi.nlm.nih.gov

Clinical applications of attenuated MVA poxvirus strain. [2013]

11. England pubmed.ncbi.nlm.nih.gov

Modified vaccinia virus Ankara as a vector for suicide gene therapy. [2020]

12. United States pubmed.ncbi.nlm.nih.gov

Long-term outcome of phase I/II clinical trial of Ad-OC-TK/VAL gene therapy for hormone-refractory metastatic prostate cancer. [2018]

13. United States pubmed.ncbi.nlm.nih.gov

Vaccination of colorectal cancer patients with modified vaccinia Ankara delivering the tumor antigen 5T4 (TroVax) induces immune responses which correlate with disease control: a phase I/II trial. [2022]

14. United States pubmed.ncbi.nlm.nih.gov

Intravenous administration of retroviral replicating vector, Toca 511, demonstrates therapeutic efficacy in orthotopic immune-competent mouse glioma model. [2022]