AGTC-501 for Retinitis Pigmentosa

Recruiting at 6 trial locations

Age: Any Age

Sex: Male

Trial Phase: Phase 2

Sponsor: Beacon Therapeutics

Disqualifiers: Other mutations, Pre-existing eye conditions, others

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

Prior Safety Data This treatment has passed at least one previous human trial

Compensation: Varies

Number of Visits: Unknown

Duration: Several weeks

24 Participants Needed

Trial Summary

What is the purpose of this trial?

This Phase 2 study is a non-randomized, open-label, study of the safety of AGTC-501 in participants with XLRP who have previously been treated with a full-length AAV vector-based gene therapy targeting RPGR protein.

Will I have to stop taking my current medications?

The trial information does not specify whether you need to stop taking your current medications. It's best to discuss this with the trial team or your doctor.

What data supports the effectiveness of the treatment AGTC-501 for Retinitis Pigmentosa?

Studies in mice and dogs with genetic mutations similar to those in humans showed that AGTC-501 helped improve the function and structure of eye cells without significant side effects. In a small human trial, some patients experienced improvements in their visual field, suggesting potential benefits of the treatment. ^{1 2 3 4 5}

What safety data exists for AGTC-501 (Laruparetigene zosaparvovec) in humans and animals?

AGTC-501 has been tested in mice, dogs, and humans, showing no significant safety concerns at lower doses. In humans, some patients experienced subretinal inflammation at higher doses, which responded to steroids, but no other major safety issues were noted. ^{1 2 3 5 6}

How is the treatment AGTC-501 unique for retinitis pigmentosa?

AGTC-501 is a gene therapy that uses a specially designed virus to deliver a corrected version of the RPGR gene directly to the retina, which is different from traditional treatments that may only manage symptoms. This approach targets the root cause of the disease by aiming to restore the function of photoreceptors, the cells in the eye that detect light. ^{1 2 3 5 7}

Eligibility Criteria

This trial is for males with X-linked Retinitis Pigmentosa who've had previous gene therapy. Participants must be at least 12, have certain levels of visual acuity and macular sensitivity, and one eye previously treated. They can't join if they have active eye infections, other genetic mutations affecting the study, a history of high eye pressure due to steroids, recent eye surgery or conditions that could complicate surgery.

Inclusion Criteria

Have detectable EZ line in the study eye as assessed by SD-OCT and confirmed by the CRC

Be able to perform all tests of visual and retinal function and structure in both eyes based on the participant's reliability and fixation, per the Investigator's discretion

I am at least 12 years old.

Exclusion Criteria

I have an active eye infection or inflammation.

I do not have genetic mutations that could affect the study treatment's effectiveness.

I do not have eye conditions that would make surgery risky or affect study results.

Timeline

Screening

Participants are screened for eligibility to participate in the trial

8 weeks

Treatment

Participants receive a single subretinal injection of AGTC-501 at either a high or low dose, followed by a corticosteroid regimen

Several weeks

Baseline visit for injection

Follow-up

Participants are monitored for safety and effectiveness after treatment, with assessments including full-field stimulus threshold and mobility tests

12 months

Long-term follow-up

Participants continue to be monitored for long-term safety and efficacy outcomes

5 years

Treatment Details

Interventions

• AGTC-501

Trial Overview The DAWN study tests AGTC-501 in two doses (low and high) combined with corticosteroids on men who've had prior RPGR-targeting gene therapy. It's an open-label Phase 2 trial where everyone knows which treatment they're getting; it's not randomized.

Participant Groups

Group I: Group 3 (High Dose, Modified Corticosteroid) Experimental Treatment 1 Intervention

Following a pars plana vitrectomy, the previously untreated eye of participants (n=approximately 3-6) will receive a central subretinal injection at the high dose in the study eye at the Baseline visit; no treatment will be administered in the previously treated fellow eye. Participants in Group 3 (high dose, modified corticosteroid) will have a more rapid corticosteroid taper.

Group II: Group 2 (Low Dose, Standard Corticosteroid) Experimental Treatment 1 Intervention

Following a pars plana vitrectomy, the previously untreated eye of participants (n=6) will receive a central subretinal injection at the low dose in the study eye at the Baseline visit; no treatment will be administered in the previously treated fellow eye. The corticosteroid taper for all treated participants in Groups 1 and 2 (high and low doses with standard corticosteroid regimen) will be a standard taper over the course of several weeks.

Group III: Group 1 (High Dose, Standard Corticosteroid) Experimental Treatment 1 Intervention

Following a pars plana vitrectomy, the previously untreated eye of participants (n=up to 12) will receive a central subretinal injection at the high dose in the study eye at the Baseline visit; no treatment will be administered in the previously treated fellow eye. The corticosteroid taper for all treated participants in Groups 1 and 2 (high and low doses with standard corticosteroid regimen) will be a standard taper over the course of several weeks.

Who Is Running the Clinical Trial?

Beacon Therapeutics

Lead Sponsor

Trials

13

Recruited

390+

Findings from Research

The rAAV vector AGTC-501, designed to deliver the RPGR gene, was well tolerated in a safety study involving 60 Rd9 mice, with no systemic toxicity or significant ocular changes observed after subretinal injection.

The study demonstrated dose-dependent expression of the RPGR protein in treated mice, supporting the potential efficacy of AGTC-501 for treating retinitis pigmentosa caused by RPGR mutations.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Toxicology and Pharmacology of an AAV Vector Expressing Codon-Optimized RPGR in RPGR-Deficient Rd9 Mice. Song, C., Conlon, TJ., Deng, WT., et al.[2020]

The first-in-human phase 1/2 clinical trial of retinal gene therapy for X-linked retinitis pigmentosa (RP) involving 18 patients showed that the treatment was generally safe, with only mild steroid-responsive inflammation noted at higher doses.

Significant visual field improvements were observed in six patients starting from one month after treatment and lasting through the 6-month follow-up, indicating potential efficacy of the gene therapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Initial results from a first-in-human gene therapy trial on X-linked retinitis pigmentosa caused by mutations in RPGR. Cehajic-Kapetanovic, J., Xue, K., Martinez-Fernandez de la Camara, C., et al.[2023]

AGTC-501, a gene therapy using a recombinant adeno-associated virus vector, was well tolerated in a study involving 16 RPGR mutant dogs, showing no systemic toxicity after subretinal injections.

The treatment demonstrated significant rescue of photoreceptor function and structure at low and mid doses, while the high dose indicated potential toxicity, establishing a safe dosage limit of 6 × 10^11 vector genomes/mL for future clinical studies in patients with X-linked retinitis pigmentosa.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Toxicity and Efficacy Evaluation of an Adeno-Associated Virus Vector Expressing Codon-Optimized RPGR Delivered by Subretinal Injection in a Canine Model of X-linked Retinitis Pigmentosa. Dufour, VL., Cideciyan, AV., Ye, GJ., et al.[2021]

In a study of 18 male patients with RPGR X-linked retinitis pigmentosa, significant thinning of the foveal photoreceptor outer segments was observed compared to 30 normal subjects, indicating a potential reason for their reduced visual acuity.

The mean outer segment thickness in RPGR patients was approximately 35.5 µm, while normal subjects had a thickness of about 61.9 µm, highlighting the need to consider these measurements when evaluating the effectiveness of retinal gene therapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Early Cone Photoreceptor Outer Segment Length Shortening in RPGR X-Linked Retinitis Pigmentosa. Menghini, M., Jolly, JK., Nanda, A., et al.[2023]

In a study involving a canine model of X-linked retinitis pigmentosa (XLRP), the rAAV2tYF-GRK1-hRPGRco gene therapy showed promising results in correcting early disease markers without significant ocular complications, except for some retinal detachment in the highest dose group.

The therapy demonstrated a dose-dependent expression of the RPGR gene and a rescue effect on retinal structure, supporting its potential for clinical trials in humans with RPGR mutations.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Dose Range Finding Studies with Two RPGR Transgenes in a Canine Model of X-Linked Retinitis Pigmentosa Treated with Subretinal Gene Therapy. Song, C., Dufour, VL., Cideciyan, AV., et al.[2021]

Gene augmentation therapy using adeno-associated virus vectors has shown effectiveness in treating canine models of X-linked retinitis pigmentosa, with preserved photoreceptor structure and function observed after treatment.

The therapy resulted in significant improvements in both rod and cone photoreceptor function, suggesting a promising pathway for future human clinical applications in treating hereditary retinal blindness.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Gene therapy rescues photoreceptor blindness in dogs and paves the way for treating human X-linked retinitis pigmentosa. Beltran, WA., Cideciyan, AV., Lewin, AS., et al.[2022]

Voretigene neparvovec-rzyl (VN) gene therapy for RPE65 mutation-associated inherited retinal dystrophy showed durable improvements in navigational ability and light sensitivity, with benefits lasting up to 4 years after treatment in a study involving 40 subjects.

The safety profile of VN therapy was consistent with the procedures used, showing no harmful immune responses, indicating it is a safe option for patients with this degenerative eye disease.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Efficacy, Safety, and Durability of Voretigene Neparvovec-rzyl in RPE65 Mutation-Associated Inherited Retinal Dystrophy: Results of Phase 1 and 3 Trials. Maguire, AM., Russell, S., Wellman, JA., et al.[2020]

References

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

Toxicology and Pharmacology of an AAV Vector Expressing Codon-Optimized RPGR in RPGR-Deficient Rd9 Mice. [2020]

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

Initial results from a first-in-human gene therapy trial on X-linked retinitis pigmentosa caused by mutations in RPGR. [2023]

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

Toxicity and Efficacy Evaluation of an Adeno-Associated Virus Vector Expressing Codon-Optimized RPGR Delivered by Subretinal Injection in a Canine Model of X-linked Retinitis Pigmentosa. [2021]

4. Switzerland pubmed.ncbi.nlm.nih.gov

Early Cone Photoreceptor Outer Segment Length Shortening in RPGR X-Linked Retinitis Pigmentosa. [2023]

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

Dose Range Finding Studies with Two RPGR Transgenes in a Canine Model of X-Linked Retinitis Pigmentosa Treated with Subretinal Gene Therapy. [2021]

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

Gene therapy rescues photoreceptor blindness in dogs and paves the way for treating human X-linked retinitis pigmentosa. [2022]

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

Efficacy, Safety, and Durability of Voretigene Neparvovec-rzyl in RPE65 Mutation-Associated Inherited Retinal Dystrophy: Results of Phase 1 and 3 Trials. [2020]