Gene Therapy for Hemophilia A

(GO-8 Trial)

Recruiting in Palo Alto (17 mi)

+3 other locations

Overseen by Pratima Chowdary

Age: 18+

Sex: Male

Travel: May Be Covered

Time Reimbursement: Varies

Trial Phase: Phase 1 & 2

Waitlist Available

Sponsor: University College, London

No Placebo Group

Trial Summary

What is the purpose of this trial?

This trial tests a gene therapy that uses a harmless virus to deliver a healthy gene to adults with severe haemophilia A. The goal is to help their bodies produce a missing blood-clotting protein, potentially curing their condition. Gene therapy for hemophilia has been explored for many years, with several programs in advanced stages.

Do I need to stop my current medications for the trial?

The trial protocol does not specify if you need to stop your current medications. However, you cannot have used investigational therapy for hemophilia within 30 days before enrollment, and you cannot be on antiviral therapy for hepatitis B or C. It's best to discuss your specific medications with the trial team.

What data supports the idea that Gene Therapy for Hemophilia A is an effective treatment?

The available research shows that Gene Therapy for Hemophilia A, specifically using the AAV8 vector, is highly effective. In a study with hemophilia A mice, AAV8 achieved 100% correction of the blood clotting issue, regardless of how it was administered. This suggests that the therapy can fully restore the necessary blood clotting factor. Compared to traditional treatments, which require frequent and costly infusions, gene therapy offers a promising alternative by potentially providing a long-term solution with fewer treatments. ^{1 2 3 4 5}

What safety data is available for the gene therapy treatment for Hemophilia A?

The safety data for the gene therapy treatment using AAV8 vectors in Hemophilia A shows promising results. Studies have demonstrated long-term efficacy and safety in both mice and dogs, with therapeutic levels of Factor VIII achieved without antibody formation or other toxicities for more than 3 years. In rhesus macaques, AAV8 vectors were well tolerated with only mild liver-related histopathology and transient elevations in transaminases. These findings support the safety of AAV8-based gene therapy for Hemophilia A. ^{2 3 6 7 8}

Is the treatment AAV2/8-HLP-FVIII-V3 a promising treatment for Hemophilia A?

Yes, AAV2/8-HLP-FVIII-V3 is a promising treatment for Hemophilia A. Research shows that using AAV8, a type of virus used to deliver the gene therapy, can fully correct the blood clotting issue in mice with Hemophilia A. This suggests that the treatment could potentially reduce the need for expensive and frequent protein replacement therapies, making it a more accessible and long-term solution for patients. ^{2 3 9 10 11}

Research Team

Pratima Chowdary

Principal Investigator

Royal Free London NHS Foundation Trust

Eligibility Criteria

Adult males over 18 with severe Hemophilia A, who have used hFVIII concentrates for more than 50 days and suffer from frequent bleeding or joint damage due to bleeding. Participants must be able to follow the trial procedures for five years and use barrier contraception post-treatment until semen tests confirm safety.

Inclusion Criteria

I am a man over 18 with severe hemophilia A due to low-risk gene mutations.

I have a severe bleeding disorder with frequent bleeding episodes or joint damage due to bleeding.

I have been treated with hFVIII for over 50 days.

Exclusion Criteria

My liver tests show higher than normal levels.

Serological evidence of HIV

My health limits my daily activities significantly.

Treatment Details

Interventions

• AAV2/8-HLP-FVIII-V3 (Virus Therapy)

Trial Overview The GO-8 study is testing a gene therapy called AAV2/8-HLP-FVIII-V3 in men with severe Hemophilia A. It aims to evaluate how safe and effective this treatment is over time.

Participant Groups

Group I: Treatment Arm Experimental Treatment 1 Intervention

Treatment with AAV2/8-HLP-FVIII-V3

Who Is Running the Clinical Trial?

University College, London

Lead Sponsor

Trials

884

Recruited

38,770,000+

Dr. Emma Morris

University College, London

Chief Medical Officer

MD from University College London

Dr. Michael Spence

University College, London

Chief Executive Officer since 2021

PhD in Chemical Engineering from University College London

Medical Research Council

Collaborator

Trials

327

Recruited

1,999,000+

Dr. Ceri Williams

Medical Research Council

Chief Medical Officer

MD

Professor Patrick Chinnery

Medical Research Council

Executive Chair

MBBS, PhD in Clinical Neuroscience

Findings from Research

AAV-mediated gene therapy for hemophilia B demonstrated sustained levels of factor IX (FIX) in patients, resulting in the near elimination of bleeding episodes for over a year.

The treatment was well-tolerated, with no serious adverse side effects reported, marking it as the most successful outcome for hemophilia gene therapy to date.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

FIX It in One Go: Enhanced Factor IX Gene Therapy for Hemophilia B. Lillicrap, D.[2019]

AAV8 was found to be the most effective serotype for liver-directed gene therapy in a hemophilia A mouse model, outperforming AAV2, AAV5, and AAV7.

Using AAV8, researchers achieved complete correction of plasma FVIII activity in mice, regardless of whether the FVIII cDNA was delivered via a single vector or two separate vectors, and regardless of the injection route (intraportal or tail vein).

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Total correction of hemophilia A mice with canine FVIII using an AAV 8 serotype. Sarkar, R., Tetreault, R., Gao, G., et al.[2021]

Gene therapy using adeno-associated virus (AAV) vectors shows promise as a potential cure for hemophilia A, which is caused by a deficiency in Factor VIII (FVIII), a crucial protein for blood clotting.

This approach could provide a safer and more cost-effective alternative to traditional protein replacement therapies, which carry risks of contamination and high expenses for patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

The treatment of hemophilia A: from protein replacement to AAV-mediated gene therapy. Youjin, S., Jun, Y.[2012]

In a study of 100 adult hemophilia A patients in the UK, 30% had preexisting immunity to AAV5 and 40% to AAV8, which could affect their response to gene therapy using these vectors.

The findings suggest that screening for antibodies against AAV5 and AAV8 is crucial to identify patients who are more likely to benefit from gene therapy, highlighting the need for further clinical studies to assess how this immunity impacts treatment safety and efficacy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Adenovirus-associated antibodies in UK cohort of hemophilia patients: A seroprevalence study of the presence of adenovirus-associated virus vector-serotypes AAV5 and AAV8 neutralizing activity and antibodies in patients with hemophilia A. Stanford, S., Pink, R., Creagh, D., et al.[2023]

A novel factor VIII molecule, ET3, was developed to enhance the biosynthesis of factor VIII, showing a 10- to 100-fold improvement in efficiency, which is crucial for gene therapy in hemophilia A.

In a study involving hemophilia A mice, a single administration of AAV-ET3 successfully corrected factor VIII deficiency at lower doses than previously required for other AAV-fVIII vectors, indicating improved potency and addressing key challenges in AAV-based gene therapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Bioengineered coagulation factor VIII enables long-term correction of murine hemophilia A following liver-directed adeno-associated viral vector delivery. Brown, HC., Wright, JF., Zhou, S., et al.[2020]

AAV6-cFVIII and AAV8-cFVIII vectors effectively restored normal levels of FVIII activity in hemophilia A mice, showing improved gene transfer efficiency compared to AAV2 and AAV5.

In hemophilia A dogs, AAV2, AAV6, and AAV8 vectors provided therapeutic FVIII levels for over 3 years without causing antibody formation or toxicities, indicating long-term safety and efficacy for potential human applications.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Multiyear therapeutic benefit of AAV serotypes 2, 6, and 8 delivering factor VIII to hemophilia A mice and dogs. Jiang, H., Lillicrap, D., Patarroyo-White, S., et al.[2022]

The AAV8.TBG.hLDLR gene therapy vector was found to be well tolerated in wild-type and heterozygous rhesus macaques, with only mild liver histopathology and transient increases in liver enzymes, indicating a favorable safety profile.

The study supports the potential use of AAV8.TBG.hLDLR for treating homozygous familial hypercholesterolemia (HoFH) and provides insights into immune responses that may occur, which could inform future clinical trials.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Non-Clinical Study Examining AAV8.TBG.hLDLR Vector-Associated Toxicity in Chow-Fed Wild-Type and LDLR+/- Rhesus Macaques. Greig, JA., Limberis, MP., Bell, P., et al.[2018]

AAV gene therapy expressing human factor V (hFVa) significantly improved hemostasis in mice with hemophilia A and B, even in the presence of FVIII inhibitors, demonstrating its potential effectiveness for patients with these conditions.

The therapy achieved complete phenotypic correction in hemophilia B mice over 28 weeks, and while minimal changes in activated partial thromboplastin time (aPTT) were noted, effective hemostasis was still observed in bleeding assays, indicating a safe profile with no increased risk of thrombosis.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Adeno-associated virus-mediated expression of activated factor V (FVa) for hemophilia phenotypic correction. Sun, J., Chen, X., Chai, Z., et al.[2022]

Gene therapy for hemophilia A has not yet achieved its potential clinical benefits, despite significant advancements in research over the past two decades.

Previous clinical trials have faced challenges in achieving sustained expression of therapeutic factor VIII, but recent improvements in gene-transfer technology and biosynthetic efficiency are paving the way for new treatment strategies.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Advancements in gene transfer-based therapy for hemophilia A. Doering, CB., Spencer, HT.[2021]

Adenovirus-mediated FVIII gene therapy in a hemophilia A mouse model showed significantly lower immune responses compared to traditional FVIII protein replacement, indicating it may be a safer treatment option.

Even in mice previously treated with FVIII protein that developed anti-FVIII antibodies, gene therapy successfully produced therapeutic levels of FVIII, suggesting it could effectively bypass the immune response that complicates protein replacement therapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Adenovirus-mediated factor VIII gene expression results in attenuated anti-factor VIII-specific immunity in hemophilia A mice compared with factor VIII protein infusion. Bristol, JA., Gallo-Penn, A., Andrews, J., et al.[2012]

A new gene therapy for hemophilia A, which targets factor VIII (FVIII) expression to platelets, demonstrated higher therapeutic efficacy compared to traditional FVIII replacement therapy, particularly in accelerating thrombin generation.

In a transgenic mouse model, a significantly lower dose of platelet-expressed FVIII (2bF8) was able to achieve similar thrombin generation levels as higher doses of plasma FVIII, indicating a more efficient hemostatic response.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Comparison of platelet-derived and plasma factor VIII efficacy using a novel native whole blood thrombin generation assay. Baumgartner, CK., Zhang, G., Kuether, EL., et al.[2023]

References

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

FIX It in One Go: Enhanced Factor IX Gene Therapy for Hemophilia B. [2019]

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

Total correction of hemophilia A mice with canine FVIII using an AAV 8 serotype. [2021]

3. Netherlands pubmed.ncbi.nlm.nih.gov

The treatment of hemophilia A: from protein replacement to AAV-mediated gene therapy. [2012]

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

Adenovirus-associated antibodies in UK cohort of hemophilia patients: A seroprevalence study of the presence of adenovirus-associated virus vector-serotypes AAV5 and AAV8 neutralizing activity and antibodies in patients with hemophilia A. [2023]

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

Bioengineered coagulation factor VIII enables long-term correction of murine hemophilia A following liver-directed adeno-associated viral vector delivery. [2020]

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

Multiyear therapeutic benefit of AAV serotypes 2, 6, and 8 delivering factor VIII to hemophilia A mice and dogs. [2022]

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

Non-Clinical Study Examining AAV8.TBG.hLDLR Vector-Associated Toxicity in Chow-Fed Wild-Type and LDLR+/- Rhesus Macaques. [2018]

8. Switzerland pubmed.ncbi.nlm.nih.gov

Adeno-associated virus-mediated expression of activated factor V (FVa) for hemophilia phenotypic correction. [2022]

9. England pubmed.ncbi.nlm.nih.gov

Advancements in gene transfer-based therapy for hemophilia A. [2021]

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

Adenovirus-mediated factor VIII gene expression results in attenuated anti-factor VIII-specific immunity in hemophilia A mice compared with factor VIII protein infusion. [2012]

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

Comparison of platelet-derived and plasma factor VIII efficacy using a novel native whole blood thrombin generation assay. [2023]