NG101 Gene Therapy for Age-Related Macular Degeneration

Recruiting at 3 trial locations

Overseen By Gisuk Chang, Pharm.D.

Age: 18+

Sex: Any

Trial Phase: Phase 1 & 2

Sponsor: Neuracle Genetics, Inc

Must be taking: Anti-VEGF injections

Must not be taking: Anticoagulant therapy

Disqualifiers: Diabetes, Glaucoma, Retinal detachment, others

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

Compensation: Varies

Number of Visits: 26

Duration: 1 day

18 Participants Needed

Trial Summary

What is the purpose of this trial?

This study will evaluate the safety, tolerability, and preliminary efficacy of NG101 AAV gene therapy administered by subretinal injections into a single selected eye as a single selected dose for patients with wet age-related macular degeneration (wAMD).

Will I have to stop taking my current medications?

The trial requires that you stop taking any anticoagulant therapy (blood thinners) that is medically necessary at least 2 weeks before the NG101 injection, except for low-dose aspirin used for prevention.

What data supports the effectiveness of the NG101 treatment for age-related macular degeneration?

Gene therapy approaches, like those used in early phase clinical trials for neovascular age-related macular degeneration, have shown promising results in delivering antiangiogenic proteins, which help reduce the need for frequent injections and related complications. ^{1 2 3 4 5}

What safety data exists for NG101 gene therapy for age-related macular degeneration?

Gene therapy using rAAV.sFlt-1 for age-related macular degeneration has shown a favorable safety profile in early clinical trials, with no drug-related adverse events reported. Some mild, procedure-related side effects were noted, such as cataracts, which were resolved with surgery. ^{2 6 7 8 9}

How is the NG101 treatment different from other treatments for age-related macular degeneration?

NG101 is a gene therapy that aims to provide a long-term solution for age-related macular degeneration by delivering anti-angiogenic proteins to the eye, potentially reducing the need for frequent injections that are common with current treatments. ^{2 3 6 10 11}

Research Team

Christopher D Riemann, MD

Principal Investigator

Neuracle Genetics, Inc. Medical Director

Eligibility Criteria

This trial is for individuals aged 50 to 89 with wet age-related macular degeneration (wAMD) in one eye, who have had at least three anti-VEGF injections in the past six months. Participants must have undergone cataract surgery and not be pregnant or able to become pregnant without contraception. They should not have any severe systemic diseases, uncontrolled glaucoma, recent ocular surgeries, other retinal diseases, or be on certain anticoagulants.

Inclusion Criteria

My vision in the study eye is between 20/63 and 20/400, mainly due to wet AMD.

I've had 3 or more anti-VEGF injections in one eye within the last 6 months.

I am using effective birth control or am not able to have children, and I have a negative pregnancy test.

Exclusion Criteria

Any medically uncontrolled diabetes, defined as HbA1C > 8.0

My study eye has had a retinal detachment.

I have had eye melanoma in the past.

Timeline

Screening

Participants are screened for eligibility to participate in the trial

1 week

1 visit (in-person)

Treatment

Participants receive a single subretinal injection of NG101 AAV gene therapy

1 day

1 visit (in-person)

Follow-up

Participants are monitored for safety and effectiveness after treatment

260 weeks

Multiple visits (in-person) at Weeks 24, 52, 104, 156, 208, and 260

Long-term follow-up

Extended monitoring for adverse events and efficacy

260 weeks

Treatment Details

Interventions

• NG101

Trial Overview The study tests NG101 AAV gene therapy given as a single dose through subretinal injection into one eye of patients with wAMD. It aims to assess the treatment's safety and initial effectiveness in improving vision affected by this condition.

Participant Groups

Group I: NG101 Gene Therapy Group 3 Experimental Treatment 1 Intervention

Single subretinal injection of 8x10\^9 vector genomes of NG101 AAV gene therapy

Group II: NG101 Gene Therapy Group 2 Experimental Treatment 1 Intervention

Single subretinal injection of 3x10\^9 vector genomes of NG101 AAV gene therapy

Group III: NG101 Gene Therapy Group 1 Experimental Treatment 1 Intervention

Single subretinal injection of 1x10\^9 vector genomes of NG101 AAV gene therapy

Who Is Running the Clinical Trial?

Neuracle Genetics, Inc

Lead Sponsor

Trials

1

Recruited

20+

ORA, Inc.

Industry Sponsor

Trials

72

Recruited

9,200+

Stuart Abelson

ORA, Inc.

Chief Executive Officer since 2007

BSc in Neuroscience from Bates College, MBA from Northwestern University

Dr. Gustavo De Moraes

ORA, Inc.

Chief Medical Officer since 2022

MD, PhD in Ophthalmic Sciences, MPH in Biostatistics

Findings from Research

In a Phase 2a trial with 32 patients suffering from wet age-related macular degeneration, the gene therapy rAAV.sFLT-1 was found to be safe, with mainly self-resolving ocular adverse events and no serious safety concerns linked to the treatment.

Patients receiving rAAV.sFLT-1 showed a median improvement in visual acuity compared to the control group, with 57% maintaining or improving vision, and they required fewer ranibizumab retreatments, suggesting that this gene therapy could be a promising option for managing wAMD.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Phase 2a Randomized Clinical Trial: Safety and Post Hoc Analysis of Subretinal rAAV.sFLT-1 for Wet Age-related Macular Degeneration. Constable, IJ., Pierce, CM., Lai, CM., et al.[2022]

Gene therapy for neovascular age-related macular degeneration (nAMD) shows promise as a long-term solution to reduce the need for frequent and costly intravitreal injections, which are currently the standard treatment.

Early phase clinical trials have reported encouraging results for gene therapy approaches, although there are ongoing debates about the best treatment targets, administration methods, and safety concerns.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Gene therapy for neovascular age-related macular degeneration: rationale, clinical trials and future directions. Guimaraes, TAC., Georgiou, M., Bainbridge, JWB., et al.[2021]

Overexpression of basic fibroblast growth factor (FGF-2) through gene transfer using a recombinant adeno-associated virus (rAAV) was tested as a potential treatment to reduce photoreceptor cell death in a model of retinal degeneration caused by constant light exposure.

The effectiveness of this treatment was evaluated using morphometric analysis and electroretinographic assessments, indicating a focus on both structural and functional outcomes in the retina.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Viral-mediated FGF-2 treatment of the constant light damage model of photoreceptor degeneration. Lau, D., Flannery, J.[2019]

The rAAV.sFLT-1 gene therapy for wet age-related macular degeneration was well tolerated in a small group of elderly patients, with no serious adverse events directly linked to the treatment, despite some reported adverse events.

While the study did not find statistically significant improvements in visual acuity, a notable percentage of patients receiving gene therapy maintained their baseline vision over three years, suggesting potential benefits that warrant further investigation.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Three-Year Follow-Up of Phase 1 and 2a rAAV.sFLT-1 Subretinal Gene Therapy Trials for Exudative Age-Related Macular Degeneration. Rakoczy, EP., Magno, AL., Lai, CM., et al.[2020]

Age-related macular degeneration (AMD) is the leading cause of blindness in the Western world, particularly affecting patients with neovascular AMD (nAMD) who currently rely on frequent and invasive anti-VEGF injections, which can lead to complications and treatment tolerance.

There is a pressing need for new therapies, especially for non-neovascular AMD, which accounts for 90% of cases and lacks approved treatments, highlighting the importance of developing improved drug delivery methods and sustainable clinical effects.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Emerging therapies and their delivery for treating age-related macular degeneration. Thomas, CN., Sim, DA., Lee, WH., et al.[2022]

KH631, a gene therapy using a recombinant adeno-associated virus vector, shows promise as a long-term treatment for neovascular age-related macular degeneration (nAMD) by enabling sustained expression of anti-VEGF proteins after a single injection.

In preclinical studies with non-human primates, a low dose of KH631 effectively prevented the formation and progression of severe choroidal neovascularization lesions for over 96 weeks, significantly reducing the treatment burden compared to frequent anti-VEGF injections.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Preclinical evaluation of KH631, a novel rAAV8 gene therapy product for neovascular age-related macular degeneration. Ke, X., Jiang, H., Li, Q., et al.[2023]

The gene therapy rAAV.sFLT-1 was found to be safe and well tolerated in a phase 1 trial involving nine patients with wet age-related macular degeneration, with no drug-related adverse events reported.

A significant portion of the treatment group (67%) did not require any rescue injections after the therapy, suggesting that a single subretinal injection could provide long-term benefits compared to the frequent injections currently needed.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Gene therapy with recombinant adeno-associated vectors for neovascular age-related macular degeneration: 1 year follow-up of a phase 1 randomised clinical trial. Rakoczy, EP., Lai, CM., Magno, AL., et al.[2022]

Adeno-associated viral vectors (AAVs) can trigger immune responses in the eye, leading to toxicity in certain ocular cell types, particularly the retinal pigment epithelium (RPE) and photoreceptors, as shown in a study using subretinal injections in mice.

The study found that the toxicity of AAVs is linked to specific cis-regulatory sequences and promoter types, with certain promoters causing damage while photoreceptor-specific promoters were safe at high doses, suggesting that careful design of AAV vectors can enhance their safety and therapeutic efficacy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

AAV cis-regulatory sequences are correlated with ocular toxicity. Xiong, W., Wu, DM., Xue, Y., et al.[2020]

In a phase 1 and 2A clinical trial involving 6 elderly patients with wet AMD, the gene therapy rAAV.sFlt-1 was found to be well tolerated with a favorable safety profile, showing no drug-related adverse events and only mild, self-resolving procedure-related issues.

Four out of six patients treated with rAAV.sFlt-1 maintained better vision and retinal health compared to the control group, suggesting that this gene therapy could serve as a promising alternative to traditional treatments like ranibizumab for wet AMD.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Gene Therapy for Age-Related Macular Degeneration. Constable, IJ., Blumenkranz, MS., Schwartz, SD., et al.[2017]

Gene therapy for neovascular age-related macular degeneration (nAMD) aims to provide a long-term solution by using adeno-associated virus (AAV) vectors to deliver anti-VEGF proteins, potentially reducing the need for frequent injections and improving visual outcomes.

Current research is focusing on optimizing gene delivery methods and exploring various therapeutic proteins, such as soluble fms-like tyrosine kinase-1 (sFLT-1) and other anti-angiogenic agents, to enhance the efficacy and safety of treatments for AMD.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Gene therapy for age-related macular degeneration. Moore, NA., Bracha, P., Hussain, RM., et al.[2018]

Transplanting pigment epithelial cells that overexpress the anti-angiogenic factor PEDF could provide a new treatment for neovascular age-related macular degeneration (nvAMD), potentially reducing the need for frequent and invasive anti-VEGF injections.

The study demonstrated successful and stable expression of the PEDF gene in primary retinal pigment epithelial cells, suggesting a promising approach for long-term therapy in nvAMD patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Engineering of PEDF-Expressing Primary Pigment Epithelial Cells by the SB Transposon System Delivered by pFAR4 Plasmids. Thumann, G., Harmening, N., Prat-Souteyrand, C., et al.[2022]

References

1. Netherlands pubmed.ncbi.nlm.nih.gov

Phase 2a Randomized Clinical Trial: Safety and Post Hoc Analysis of Subretinal rAAV.sFLT-1 for Wet Age-related Macular Degeneration. [2022]

2. England pubmed.ncbi.nlm.nih.gov

Gene therapy for neovascular age-related macular degeneration: rationale, clinical trials and future directions. [2021]

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

Viral-mediated FGF-2 treatment of the constant light damage model of photoreceptor degeneration. [2019]

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

Three-Year Follow-Up of Phase 1 and 2a rAAV.sFLT-1 Subretinal Gene Therapy Trials for Exudative Age-Related Macular Degeneration. [2020]

5. England pubmed.ncbi.nlm.nih.gov

Emerging therapies and their delivery for treating age-related macular degeneration. [2022]

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

Preclinical evaluation of KH631, a novel rAAV8 gene therapy product for neovascular age-related macular degeneration. [2023]

7. England pubmed.ncbi.nlm.nih.gov

Gene therapy with recombinant adeno-associated vectors for neovascular age-related macular degeneration: 1 year follow-up of a phase 1 randomised clinical trial. [2022]

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

AAV cis-regulatory sequences are correlated with ocular toxicity. [2020]

9. China pubmed.ncbi.nlm.nih.gov

Gene Therapy for Age-Related Macular Degeneration. [2017]

10. England pubmed.ncbi.nlm.nih.gov

Gene therapy for age-related macular degeneration. [2018]

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

Engineering of PEDF-Expressing Primary Pigment Epithelial Cells by the SB Transposon System Delivered by pFAR4 Plasmids. [2022]