Gene Therapy for Hemophilia A

(GO-8 Trial)

Not currently recruiting at 3 trial locations

Overseen By Pratima Chowdary

Age: 18+

Sex: Male

Trial Phase: Phase 1 & 2

Sponsor: University College, London

Must be taking: hFVIII concentrates

Must not be taking: Antivirals, Investigational therapies

Disqualifiers: HIV, Liver dysfunction, Hypertension, others

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

Compensation: Varies

Number of Visits: 6

Duration: 1 day

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial explores a gene therapy for severe hemophilia A, aiming to improve the safety and effectiveness of this new treatment. Participants will receive an experimental therapy designed to enhance the body's production of a crucial blood-clotting protein. Men with a confirmed diagnosis of severe hemophilia A who experience frequent bleeding episodes or joint issues might be suitable candidates. As a Phase 1 trial, the research focuses on understanding how the treatment works in people, offering participants the opportunity to be among the first to receive this innovative therapy.

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.

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

Research shows that the gene therapy treatment AAV2/8-HLP-FVIII-V3 has promising safety results. In previous studies, this treatment maintained stable levels of Factor VIII, a protein that helps blood clot, for up to five years in people with severe hemophilia A. This indicates that the treatment functions as intended.

However, some participants experienced side effects, including reactions to the infusion, serious health issues, and changes in liver enzyme levels. Monitoring liver enzymes is important because changes can signal liver stress. These side effects were observed and managed during the studies.

Overall, while some risks exist, many people have tolerated the therapy well. Staying informed and discussing any concerns with healthcare professionals before joining a trial is crucial. ^{1 2 3 4 5}

Why do researchers think this study treatment might be promising?

Unlike the standard treatments for hemophilia A, which often involve regular infusions of clotting factor VIII, the investigational therapy AAV2/8-HLP-FVIII-V3 offers a potentially transformative approach by using gene therapy. This treatment delivers a functional copy of the gene responsible for producing factor VIII directly into the patient's liver cells, potentially allowing them to produce the protein on their own. Researchers are excited because this method could significantly reduce or even eliminate the need for frequent factor VIII infusions, offering a more lasting solution for managing hemophilia A.

What evidence suggests that this gene therapy might be an effective treatment for hemophilia A?

Research has shown that the gene therapy AAV2/8-HLP-FVIII-V3, which participants in this trial will receive, could be a promising treatment for severe hemophilia A. Studies have found that a single dose of this therapy can lead to stable production of Factor VIII, a crucial protein for blood clotting, for up to 5 years. Extensive studies in animals, such as mice and primates, support its long-term effectiveness. Early human trials demonstrated similar results, suggesting this therapy could significantly enhance blood clotting in people with hemophilia A. These findings offer hope for reducing bleeding episodes and improving the quality of life for those affected. ^{1 2 3 4 5}

Who Is on the Research Team?

Pratima Chowdary

Principal Investigator

Royal Free London NHS Foundation Trust

Are You a Good Fit for This Trial?

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.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Single systemic administration of AAV2/8-HLP-FVIII-V3 gene therapy

1 day

1 visit (in-person)

Follow-up

Participants are monitored for safety and effectiveness after treatment, including assessments of plasma hFVIII activity, bleeding frequency, and immune response

5 years

Regular visits up to 5 years post-infusion

What Are the Treatments Tested in This Trial?

Interventions

• AAV2/8-HLP-FVIII-V3

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.

How Is the Trial Designed?

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+

Medical Research Council

Collaborator

Trials

327

Recruited

1,999,000+

Published Research Related to This Trial

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]

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]

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]

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]

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]

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]

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]

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]

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]

Citations

1. ashpublications.org ashpublications.org/blood/article/142/Supplement%201/3624/500955/GO-8-Stable-Expression-of-Factor-VIII-over-5-Years

GO-8: Stable Expression of Factor VIII over 5 Years Following ... Conclusion: A single infusion of AAV-HLP-hFVIII-V3 resulted in stable FVIII expression over a follow-up period of up to 5 years in participants ...

2. clinicaltrials.gov clinicaltrials.gov/study/NCT03001830

NCT03001830 | Gene Therapy for Haemophilia A. Extensive preclinical studies demonstrate that AAV2/8-HLP-FVIII-V3 leads to long-term, endogenous expression of FVIII in mouse and non-human primate models ...

3. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC9821304/

Gene therapy for hemophilia - PMC - PubMed Central - NIH GO-8: preliminary results of a phase I/II dose escalation trial of gene therapy for haemophilia a using a novel human factor VIII variant.

4. ashpublications.org ashpublications.org/bloodadvances/article/8/23/5957/518100/Adeno-associated-virus-based-gene-therapy-for

Adeno-associated virus–based gene therapy for hemophilia A ... Specifically, for the efficacy outcomes, pooled point estimates were obtained for the pretherapy and posttherapy mean differences. Studies ...

5. sciencedirect.com sciencedirect.com/science/article/abs/pii/S0006497123102266

GO-8: Stable Expression of Factor VIII over 5 Years ... A single infusion of AAV-HLP-hFVIII-V3 resulted in stable FVIII expression over a follow-up period of up to 5 years in participants with severe haemophilia A.