Gene Therapy for Hemophilia B

(BEYOND-9 Trial)

Recruiting at 11 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

Trial Summary

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.

What data supports the effectiveness of the treatment REGV131-LNP1265 for hemophilia B?

Research shows that gene therapy can restore the production of clotting factor IX (FIX) in hemophilia B, reducing bleeding. A study using a similar approach with lipid nanoparticles (LNP) and adeno-associated virus (AAV) demonstrated sustained FIX production and normal blood clotting in mice, suggesting potential effectiveness for this treatment. ^{1 2 3 4 5}

Is gene therapy for Hemophilia B generally safe in humans?

Gene therapy for Hemophilia B, including treatments like AMT-060 and AMT-061, has shown a favorable safety profile in studies, with no severe side effects reported in non-human primates and no T cell-mediated liver toxicity in humans. Another study using a combination of viral and non-viral vectors also reported no severe side effects, except for some random genetic integrations. ^{1 5 6 7 8}

How is the treatment REGV131-LNP1265 unique for hemophilia B?

REGV131-LNP1265 is unique because it combines gene therapy with lipid nanoparticles (LNPs) and adeno-associated virus (AAV) to edit genes and restore normal blood clotting in hemophilia B, potentially offering long-term benefits with a single treatment, unlike traditional therapies that require frequent administration. ^{1 2 3 5 8}

What is the purpose of this trial?

Participants in this study have a genetic mutation, specifically in the coagulation (blood clotting) Factor 9 gene that causes severe or moderately severe hemophilia B. 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 insertion therapy aims to teach the body how to produce clotting factor long-term, without the need for factor replacement therapy. The main aim of this study is to find a safe and well-tolerated dose of the study drug by checking the side effects that may happen from taking it. The study is looking at several other research questions including: * How much study drug is in the blood at different times * Whether the body makes antibodies against parts of the study drug, which could make the drug less effective or could lead to side effects. Antibodies are proteins produced by the body's immune system in response to a foreign substance * Whether the body makes antibodies against the clotting factor replacement therapy * How quality of life is affected by hemophilia B and if it changes after taking study drug * How joint health is affected by hemophilia B and if it changes after taking study drug * How often visits are required for the emergency room, urgent care center, physician's office, hospital, telephone or online are required as a result of bleeding events, and if the frequency changes after taking study drug * How often factor replacement therapy is needed, both on a regular basis for prevention of bleeding, and as needed to treat bleeding events (and it if changes after taking study drug) * Whether there is a difference in 2 different methods for measuring Factor 9 activity in the blood

Research Team

Clinical Trial Management

Principal Investigator

Regeneron Pharmaceuticals

Eligibility Criteria

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

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

Treatment Details

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.

Participant Groups

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+

Findings from Research

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]

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]

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]

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]

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]

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]

References

1. China pubmed.ncbi.nlm.nih.gov

[Lasting expression of hF IX mediated by myoblasts in mice]. [2012]

2. United States 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. [2022]

3. Switzerland pubmed.ncbi.nlm.nih.gov

Gene Therapy Approaches for the Treatment of Hemophilia B. [2023]

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

Developments in the treatment of hemophilia B: focus on emerging gene therapy. [2021]

5. United States 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. [2023]

6. United States 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. [2020]

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

Neonatal Gene Therapy for Hemophilia B by a Novel Adenovirus Vector Showing Reduced Leaky Expression of Viral Genes. [2020]

8. England 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. [2022]