Gene Therapy for Hemophilia A

Overseen By Clinical Trial Manager, PhD

Age: 18+

Sex: Male

Trial Phase: Phase 1 & 2

Sponsor: ASC Therapeutics

Must be taking: FVIII replacement

Must not be taking: Anticoagulants, Antivirals

Disqualifiers: Liver fibrosis, Renal disease, Infections, others

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

Compensation: Varies

Number of Visits: Unknown

Duration: 12 weeks

12 Participants Needed

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial tests a new gene therapy for hemophilia A, a condition where blood doesn't clot properly, causing excessive bleeding. The goal is to determine if this treatment can safely and effectively reduce the need for frequent injections required by current treatments. The trial uses a gene therapy called ASC618, which aims to help the liver produce a protein needed for blood clotting. Men with severe or moderately severe hemophilia A who have experienced frequent bleeding episodes and have been on preventive or on-demand therapy 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 new therapy.

Will I have to stop taking my current medications?

The trial information does not specify if you need to stop taking your current medications. However, if you are on antiviral therapy for hepatitis B or C, you may not be eligible to participate.

Is there any evidence suggesting that ASC618 is likely to be safe for humans?

Research has shown that gene therapies, such as ASC618 for hemophilia A, are becoming safer and more effective. Although ASC618 lacks long-term safety data, similar gene therapies offer some reassurance. For instance, one study on another gene therapy for hemophilia followed patients for 13 years and found lasting benefits with manageable side effects. Another study tracked patients for two years and reported good safety results, with most participants experiencing fewer bleeding episodes.

As ASC618 is in the early stages of testing, researchers are focusing on its safety. They closely monitor participants for any side effects or reactions. It is important to know that this treatment undergoes careful review to ensure its safety. ^{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 factors, ASC618 is unique because it is a gene therapy. Researchers are excited about ASC618 because it offers the potential for long-term correction of the condition by introducing a functional copy of the gene responsible for producing the missing or defective clotting factor. This approach could significantly reduce or even eliminate the need for ongoing factor replacement therapy, offering a more sustainable and convenient solution for patients.

What evidence suggests that ASC618 might be an effective treatment for hemophilia A?

Research has shown that gene therapy for hemophilia A can greatly reduce bleeding episodes. For instance, patients who received a similar gene therapy, valoctocogene roxaparvovec, experienced 84% fewer joint bleeds after 24 months. This demonstrates that gene therapy can effectively lower bleeding rates. The trial is studying ASC618, a treatment that uses a harmless virus to deliver genes enabling the liver to produce factor VIII, a protein that aids blood clotting. Early animal studies have shown promising safety and effectiveness. These initial results suggest that ASC618 might offer a longer-lasting solution for people with hemophilia A. ^{3 6 7 8 9}

Are You a Good Fit for This Trial?

This trial is for male adults over 18 with severe or moderately severe hemophilia A, experiencing at least 12 bleeding episodes a year if on-demand therapy. They must have used replacement therapy for over 150 days and have a BMI of ≤30. Participants need to commit to using double-barrier contraception post-treatment until semen tests are negative.

Inclusion Criteria

Agree to use double-barrier contraceptive until at least 3 consecutive semen samples are negative after ASC-618 infusion

BMI ≤ 30

I have received FVIII therapy for at least 150 days.

Exclusion Criteria

Evidence of active Hepatitis B, Hepatitis C, Human Immunodeficiency Virus (HIV)-1/2 or syphilis infection

I am currently on medication for hepatitis B or C.

I have or had high levels of Factor VIII inhibitors.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive ASC618 gene therapy to evaluate safety and preliminary efficacy

12 weeks

Follow-up

Participants are monitored for safety and effectiveness after treatment

24 weeks

What Are the Treatments Tested in This Trial?

Interventions

• ASC618

Trial Overview The study is testing ASC618, an advanced gene therapy designed to deliver a corrected form of the factor VIII gene to patients with hemophilia A. The goal is to reduce the frequency of bleeding episodes and treatment injections by enabling sustained production of factor VIII in the body.

How Is the Trial Designed?

Group I: ASC618 Experimental Treatment 1 Intervention

Experimental Arm

Who Is Running the Clinical Trial?

ASC Therapeutics

Lead Sponsor

Trials

2

Recruited

70+

Published Research Related to This Trial

Gene therapy for hemophilia aims to cure the condition by providing a functional copy of the defective gene responsible for producing blood clotting factors, which can significantly reduce bleeding episodes with just a small increase in factor levels (≥2% of normal).

Recent trials, including seven early-phase studies involving over 55 patients with hemophilia A and B, have shown promising results, indicating that gene therapy is moving closer to market authorization as a viable treatment option.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Advances in Gene Therapy for Hemophilia. Nathwani, AC., Davidoff, AM., Tuddenham, EGD.[2018]

Gene therapy for hemophilia A and B has shown promising results in preclinical studies, achieving long-term correction of bleeding disorders in animal models using viral vectors.

Phase I clinical trials in humans with severe hemophilia A or B are underway, and preliminary data suggest that gene therapy could potentially provide a cure, marking a significant advancement in treatment options for these conditions.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Viral vector-mediated gene therapy for hemophilia. VandenDriessche, T., Collen, D., Chuah, MK.[2019]

In a study involving 10 adults with severe hemophilia B, a single infusion of the gene therapy AMT-060 led to significant increases in endogenous factor IX (FIX) activity, with mean levels reaching 4.4 IU/dL in the low-dose group and 6.9 IU/dL in the high-dose group, resulting in an 81% and 73% reduction in FIX concentrate use, respectively.

The therapy demonstrated a positive safety profile, with only limited and transient elevations in liver enzymes that were asymptomatic and manageable, while effectively reducing spontaneous bleeding rates by 53% and 70% in the respective dose cohorts.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Gene therapy with adeno-associated virus vector 5-human factor IX in adults with hemophilia B. Miesbach, W., Meijer, K., Coppens, M., et al.[2021]

Gene transfer has shown promise as a safe and well-tolerated treatment for hemophilia A and B, based on results from four completed phase I clinical trials and two ongoing trials.

Current research is focused on enhancing the efficiency of gene transfer techniques to improve treatment outcomes for patients with hemophilia.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Hemophilia gene therapy: update. Monahan, PE., White, GC.[2019]

Gene therapy for haemophilia B has shown promising results, with a single intravenous treatment leading to a long-term increase in therapeutic levels of factor IX (FIX) for over 4 years without significant toxicity.

This approach offers a potential cure compared to traditional clotting factor replacement therapy, which is costly and requires lifelong administration, but challenges remain before gene therapy can be widely implemented.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Haemophilia gene therapy: Progress and challenges. Lheriteau, E., Davidoff, AM., Nathwani, AC.[2022]

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]

AMT-060, a gene therapy for severe hemophilia B, demonstrated sustained factor IX (FIX) activity of 3%-13% and significantly reduced spontaneous bleeding without causing T cell-mediated liver toxicity in patients.

The modified version, AMT-061, showed a 6.5-fold increase in FIX activity compared to AMT-060 in non-human primates, while maintaining a similar safety profile, indicating its potential as a more effective treatment option.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Enhanced Factor IX Activity following Administration of AAV5-R338L "Padua" Factor IX versus AAV5 WT Human Factor IX in NHPs. Spronck, EA., Liu, YP., Lubelski, J., et al.[2020]

Gene therapy for hemophilia aims to improve or cure the condition by increasing levels of deficient coagulation factors through the use of liver-directed adeno-associated viral vectors, with several programs currently in phase 3 trials.

There is a critical need for long-term data collection on the safety and efficacy of these gene therapies, which is being coordinated by organizations like the American Thrombosis and Hemostasis Network and the World Federation of Hemophilia to ensure optimal treatment outcomes for patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

The critical need for postmarketing surveillance in gene therapy for haemophilia. Konkle, BA., Recht, M., Hilger, A., et al.[2021]

Gene therapy for Hemophilia A aims to provide a single treatment that enables the body to produce its own Factor VIII (FVIII), potentially leading to significant improvements in bleeding protection and quality of life for patients.

The BAY 2599023 gene therapy product, which uses a specific AAV vector, shows promise due to its low prevalence of anti-AAV-hu37 antibodies, which may enhance patient eligibility and safety compared to other AAV-based therapies.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Characteristics of BAY 2599023 in the Current Treatment Landscape of Hemophilia A Gene Therapy. Pipe, SW., Arruda, VR., Lange, C., 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]

A single injection of a helper-dependent adenoviral vector (HDV) in three hemophilia A dogs resulted in significant improvements in blood clotting measures, with two dogs achieving near-normal clotting times and no bleeding events reported after treatment.

While there were transient increases in liver enzymes and thrombocytopenia following the injection, these side effects resolved within two weeks, indicating that the treatment is generally safe despite some initial toxicity.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Helper-dependent adenoviral gene therapy mediates long-term correction of the clotting defect in the canine hemophilia A model. McCORMACK, WM., Seiler, MP., Bertin, TK., et al.[2023]

Recent advancements in gene therapy for hemophilia A and B, particularly using adeno-associated virus (AAV) vectors, have shown promising results in increasing factor VIII and IX levels, leading to a significant reduction in bleeding episodes and the need for prophylactic treatments in most patients.

While the clinical benefits of gene therapy are evident, ongoing trials also highlight potential side effects and limitations that need to be addressed before these therapies can be widely implemented for hemophilia patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Gene therapy for hemophilia: a review on clinical benefit, limitations, and remaining issues. Leebeek, FWG., Miesbach, W.[2021]

Citations

1. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC10387967/

The effectiveness and value of gene therapy for hemophilia At 24 months, patients treated with valoctocogene roxaparvovec had an 84% reduction in treated joint bleeds and similar reductions in other treated bleeds when ...

2. jmcp.org jmcp.org/doi/10.18553/jmcp.2024.30.10.1178

A systematic review of cost-effectiveness analyses of gene ... The novel hemophilia gene therapy treatments can potentially be a cost-effective use of treatment resources if the treatment effects are durable over time.

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

Two-Year Outcomes of Valoctocogene Roxaparvovec ... Among adult men with severe hemophilia A, a significant reduction in the annualized bleeding rates as compared with those reported with previous ...

4. sciencedirect.com sciencedirect.com/science/article/pii/S2475037925002729

Why is the uptake of gene therapy in hemophilia less than ... However, a functional cure, defined as permanent factor levels of at least 40%, has seen durable success in some FIX gene therapy recipients. Less success has ...

5. asctherapeutics.com asctherapeutics.com/wp-content/uploads/2021/10/ASGCT-2020-poster_final.pdf

Preclinical Development of ASC-618, an Advanced Human ... Here we present the results of safety and efficacy experiments comparing ET3 with HSQ in three species, namely C57Bl/6 murine model, cynomolgus monkeys and ...

6. clinicaltrials.gov clinicaltrials.gov/study/NCT04676048

ASC618 Gene Therapy in Hemophilia A Patients A phase of research to describe clinical trials that focus on the safety of a drug. They are usually conducted with healthy volunteers, and the goal is to ...

7. pubmed.ncbi.nlm.nih.gov pubmed.ncbi.nlm.nih.gov/40499172/

Sustained Clinical Benefit of AAV Gene Therapy in Severe ... Data on safety and durability from 13 years of follow-up in a cohort of patients who had been successfully treated with scAAV2/8-LP1-hFIXco gene ...

8. bleeding.org bleeding.org/news/nejm-publishes-follow-up-data-on-hemophilia-b-gene-therapy-product

Follow-up Trial Data on Hemophilia B Gene Therapy Now ... A newly published paper includes safety and efficacy data in hemophilia B patients who have received BEQVEZ.

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

Three-year outcomes of valoctocogene roxaparvovec gene ... During year 3, 74.5% of rollover participants had 0 treated bleeds compared with 32.1% during baseline on FVIII prophylaxis, 82.1% during year 1, and 83.9% ...