Gene Therapy for Hemophilia B

(BEYOND-9 Trial)

Recruiting at 31 trial locations

Overseen By Clinical Trials Administrator

Age: 18+

Sex: Male

Trial Phase: Phase 1 & 2

Sponsor: Regeneron Pharmaceuticals

Must be taking: FIX prophylaxis

Must not be taking: Corticosteroids

Disqualifiers: Liver disease, Thrombo-embolic events, others

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

Compensation: Varies

Number of Visits: Unknown

130 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 individuals with severe or moderately severe hemophilia B, a condition where blood doesn't clot properly due to a Factor 9 gene mutation. The main goal is to determine a safe dose of the study drug, REGV131-LNP1265, which might enable the body to produce its own clotting factor and reduce the need for regular treatments. Participants will provide researchers with insights into the drug's safety, side effects, and its impact on quality of life and joint health. Eligible participants should currently be on Factor 9 treatments and have a history of severe hemophilia B.

As a Phase 1/Phase 2 trial, this study aims to understand how the treatment works in people and assess its effectiveness in an initial, smaller group, offering participants a chance to contribute to groundbreaking research.

Will I have to stop taking my current medications?

The trial does not specify if you need to stop taking your current medications. However, it mentions that participants should currently be taking FIX prophylaxis (regular treatment to prevent bleeding) and have previous experience with FIX therapy.

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

Research has shown that REGV131-LNP1265, a new gene therapy for hemophilia B, has been tested for safety in people. Although specific results from these studies are not available, the therapy's presence in early clinical trials indicates it has passed some initial safety tests.

Early trials aim to find a safe dose and check for side effects, meaning the therapy has undergone basic safety checks. Participants in these trials receive close monitoring for any side effects. The goal is to ensure the therapy does not cause serious harm and that any side effects remain manageable.

REGV131-LNP1265 is designed to help the body produce clotting factor, crucial for people with hemophilia B. While this therapy is not yet approved, ongoing research continues to clarify its safety and potential benefits. Those considering joining a trial should discuss the possible risks and benefits with their healthcare provider. ^{1 2 3 4 5}

Why do researchers think this study treatment might be promising?

Unlike standard treatments for hemophilia B, which typically involve regular infusions of clotting factor IX (FIX) concentrates, REGV131-LNP1265 is a gene therapy aiming to provide a long-term solution by correcting the underlying genetic issue. This innovative approach uses lipid nanoparticles to deliver a functional copy of the FIX gene directly into the patient's cells, potentially reducing or eliminating the need for frequent infusions. Researchers are excited about this treatment because it offers the possibility of sustained FIX production in the body, which could lead to fewer bleeding episodes and improved quality of life for patients.

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

Research has shown that gene therapy for hemophilia B, such as REGV131-LNP1265, holds promise. In this trial, participants will receive varying doses of REGV131-LNP1265 to determine the recommended dose for efficacy (RDE). Studies have found that patients achieved an average of 37% of normal Factor IX (FIX) activity, which remained stable for one to two years. This is significant because FIX is the protein necessary for blood clotting, and higher levels result in fewer bleeding episodes. The therapy employs CRISPR/Cas9, a method that enables the body to produce FIX independently. Early results suggest this could reduce or eliminate the need for regular clotting factor injections. Thus far, it appears effective in enhancing clotting ability and reducing bleeding risk. ^{1 2 4 6 7}

Who Is on the Research Team?

Clinical Trial Management

Principal Investigator

Regeneron Pharmaceuticals

Are You a Good Fit for This Trial?

This trial is for pediatric, adolescent, and adult patients with severe or moderately severe hemophilia B. Participants must have a confirmed diagnosis with Factor IX activity ≤2% or a genotype causing severe hemophilia B. They should be currently on FIX prophylaxis and have prior experience with FIX therapy.

Inclusion Criteria

I have been part of this study or a related study for at least 6 months.

I am currently on FIX prophylaxis and have used FIX therapy before.

I have severe or moderately severe hemophilia B.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Dose Escalation and Dose Confirmation

Dose escalation cohorts to determine the recommended dose for expansion (RDE) of REGV131-LNP1265 and dose confirmation to gain further confidence in safety, tolerability, and Coagulation Factor IX (FIX) functional activity data at the RDE

Up to 104 weeks

Multiple visits for dose administration and monitoring

Dose Expansion

Participants receive the recommended dose for expansion (RDE) of REGV131-LNP1265, with different cohorts for adults, adolescents, and pediatric patients

Up to 104 weeks

Regular visits for monitoring and assessment

Follow-up

Participants are monitored for safety and effectiveness after treatment, including assessment of FIX functional activity and annualized bleeding rate

52 weeks

Periodic visits for follow-up assessments

What Are the Treatments Tested in This Trial?

Interventions

• REGV131-LNP1265

Trial Overview The study tests REGV131-LNP1265, an experimental gene insertion therapy designed to help the body produce clotting factor long-term in people with hemophilia B. It aims to find a safe dose by monitoring side effects and how it affects quality of life, joint health, bleeding events frequency, and need for replacement therapy.

How Is the Trial Designed?

Group I: Part 2: Dose Expansion C Experimental Treatment 2 Interventions

Participants ≥2 to \<12 Years of Age will receive the administered weight-adjusted RDE of REGV131-LNP1265 determined by Part 1

Group II: Part 2: Dose Expansion B Experimental Treatment 2 Interventions

Participants ≥12 to \<18 Years of Age will receive the administered weight-adjusted RDE of REGV131-LNP1265 determined by Part 1

Group III: Part 2: Dose Expansion A Experimental Treatment 2 Interventions

Participants ≥18 Years of Age will receive the RDE of REGV131-LNP1265 determined by Part 1

Group IV: Part 1: Cohort 4 Dose Escalation for RDE Experimental Treatment 2 Interventions

Dose 4 of ascending dose level cohorts to determine the RDE of REGV131-LNP1265 and further assess the safety, tolerability, and FIX functional activity data at the RDE

Group V: Part 1: Cohort 3 Dose Escalation for RDE Experimental Treatment 2 Interventions

Dose 3 of ascending dose level cohorts to determine the RDE of REGV131-LNP1265 and further assess the safety, tolerability, and FIX functional activity data at the RDE

Group VI: Part 1: Cohort 2 Dose Escalation for RDE Experimental Treatment 2 Interventions

Dose 2 of ascending dose level cohorts to determine the RDE of REGV131-LNP1265 and further assess the safety, tolerability, and FIX functional activity data at the RDE

Group VII: Part 1: Cohort 1 Dose Escalation for RDE Experimental Treatment 2 Interventions

Starting dose to determine the RDE of REGV131-LNP1265 and further assess the safety, tolerability, and FIX functional activity data at the RDE

Who Is Running the Clinical Trial?

Regeneron Pharmaceuticals

Lead Sponsor

Trials

690

Recruited

948,000+

Founded

1988

Headquarters

Tarrytown, USA

Known For

Precision medicine

Top Products

Dupixent, EYLEA, Libtayo, Praluent

Leonard Schleifer

Regeneron Pharmaceuticals

Chief Executive Officer since 1988

MD and PhD in Medicine

George Yancopoulos

Regeneron Pharmaceuticals

Chief Medical Officer since 1997

MD from Harvard Medical School

Intellia Therapeutics

Industry Sponsor

Trials

10

Recruited

1,300+

Published Research Related to This Trial

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 B has shown promise, particularly with a novel adeno-associated virus vector that successfully increased clotting factor IX (FIX) levels in patients, potentially changing severe hemophilia to a milder form.

The research highlights the importance of understanding how different viral vectors interact with the immune system, which is crucial for improving gene therapy effectiveness and minimizing immune responses in future treatments.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Developments in the treatment of hemophilia B: focus on emerging gene therapy. Cancio, MI., Reiss, UM., Nathwani, AC., et al.[2021]

The novel adenovirus vector Ad-E4-122aT showed significantly higher transduction efficiencies in neonatal hemophilia B mice compared to conventional vectors, indicating its potential for effective gene therapy.

A single injection of Ad-E4-122aT expressing human factor IX maintained therapeutic levels of the protein for about 100 days, and sequential doses resulted in levels exceeding normal, effectively rescuing bleeding symptoms in the mice.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Neonatal Gene Therapy for Hemophilia B by a Novel Adenovirus Vector Showing Reduced Leaky Expression of Viral Genes. Iizuka, S., Sakurai, F., Tachibana, M., et al.[2020]

A novel therapeutic strategy for hemophilia B was developed using a combination of lipid nanoparticles (LNP) and adeno-associated virus (AAV) to downregulate antithrombin and integrate human factor IX (hF9) gene, resulting in a significant reduction of antithrombin levels and restoration of normal coagulation activity.

The treatment led to sustained production of hFIX for up to 63 weeks with minimal side effects, demonstrating the potential for long-term management of hemophilia B through this innovative gene editing approach.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

In&#160;vivo genome editing for hemophilia B therapy by the combination of rebalancing and therapeutic gene knockin using a viral and non-viral vector. Lee, JH., Han, JP., Song, DW., et al.[2023]

Gene therapy for hemophilia B was successfully developed using C2C12 cells and C3H mice, demonstrating that the expression of the hF IX protein in vivo increased with the number of injected cells.

The study found that using immunosuppressive agents could enhance and prolong the expression of hF IX, suggesting that managing immune responses may improve the effectiveness of myoblast-mediated gene therapy for hemophilia B.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[Lasting expression of hF IX mediated by myoblasts in mice]. Wang, H., Yang, X., Bao, Y., et al.[2012]

A novel platelet gene therapy for hemophilia B using lentivirus-transduced hematopoietic stem cells showed sustained expression of factor IX (FIX) in 6-39% of platelets, effectively correcting bleeding issues in FIX(null) mice.

The therapy not only restored normal blood clotting but also induced immune tolerance, as none of the treated mice developed anti-FIX antibodies, suggesting a promising potential for human applications.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Platelet gene therapy by lentiviral gene delivery to hematopoietic stem cells restores hemostasis and induces humoral immune tolerance in FIX(null) mice. Chen, Y., Schroeder, JA., Kuether, EL., et al.[2022]

Gene therapy for hemophilia B, using a single injection of adeno-associated viral (AAV) vectors, can restore and maintain F9 gene expression for a much longer duration compared to standard enzyme-replacement therapy, which requires frequent administration.

Research is ongoing to enhance the efficiency of gene delivery and expression, as well as exploring CRISPR/Cas9 technology for potential genome editing as a treatment option for hemophilia B.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Gene Therapy Approaches for the Treatment of Hemophilia B. Soroka, AB., Feoktistova, SG., Mityaeva, ON., et al.[2023]

In a pilot study involving 10 adult males with hemophilia B, the liver-targeted gene therapy BBM-H901 was found to be safe, with no serious adverse events reported after a median follow-up of 58 weeks.

The treatment significantly increased factor IX levels to a mean of 36.9 IU/dL, which is sufficient to prevent bleeding events and reduce the need for traditional replacement therapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Safety and activity of an engineered, liver-tropic adeno-associated virus vector expressing a hyperactive Padua factor IX administered with prophylactic glucocorticoids in patients with haemophilia B: a single-centre, single-arm, phase 1, pilot trial. Xue, F., Li, H., Wu, X., et al.[2022]

Citations

1. clinicaltrials.gov clinicaltrials.gov/study/NCT06379789

NCT06379789 | A Study to Investigate the Safety and ... This study is researching an experimental gene insertion therapy (the adding of a gene into your DNA) called REGV131-LNP1265, also called the study drug.

2. sciencedirect.com sciencedirect.com/science/article/pii/S1525001625002175

Gene therapy for hemophilia – From basic science to first ... With an average follow-up of more than a year, the mean FIX activity was 37% normal and appeared stable between years 1 and 2. Nine of the 10 ...

3. clinicaltrials.eu clinicaltrials.eu/trial/study-on-the-safety-and-effectiveness-of-regv131-and-lnp1265-for-adults-with-hemophilia-b/

Study on the Safety and Effectiveness of REGV131 ... This clinical trial investigates the safety and effectiveness of the REGV131-LNP1265 treatment, utilizing the CRISPR/Cas9 method, for the production of ...

4. chop.edu chop.edu/research-studies/regeneron-pharmaceuticals-hemophilia-b-gene-therapy-trial

Regeneron Pharmaceuticals Hemophilia B Gene Therapy ... The main goal of this study is to learn if Regeneron Pharmaceuticals' gene therapy product, REGV131-LNP1265, improves patients with Hemophilia B's ability to ...

5. uclahealth.org uclahealth.org/clinical-trials/study-investigate-safety-and-effectiveness-coagulation

Blood Disorders UCLA Clinical Trial | A Study to Investigate ... This study is researching an experimental gene insertion therapy (the adding of a gene into your DNA) called REGV131-LNP1265, also called the "study drug". Gene ...

6. clinicaltrials.ucsf.edu clinicaltrials.ucsf.edu/trial/NCT06379789

Coagulation Factor IX Gene Insertion Therapy (REGV131- ... This study is researching an experimental gene insertion therapy (the adding of a gene into your DNA) called REGV131-LNP1265, also called the study drug.

7. connect.careboxhealth.com connect.careboxhealth.com/en-US/trial/listing/485295

A Study to Investigate the Safety and Effectiveness ... This study is researching an experimental gene insertion therapy (the adding of a gene into your DNA) called REGV131-LNP1265, also called the " ...