AGTC-501 for Retinitis Pigmentosa

Recruiting at 5 trial locations

Age: < 65

Sex: Male

Trial Phase: Phase 2

Sponsor: Beacon Therapeutics

Must not be taking: Anticoagulants, Corticosteroids, Immunosuppressives, Antivirals

Disqualifiers: Herpes, Immunosuppression, Systemic infection, 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: Single occasion

14 Participants Needed

Trial Summary

What is the purpose of this trial?

This study will evaluate the safety and efficacy of a recombinant adeno-associated virus vector (rAAV2tYF-GRK1-RPGR) in patients with X-linked retinitis pigmentosa caused by RPGR mutations.

Will I have to stop taking my current medications?

The trial does not specify if you need to stop taking your current medications, but you cannot participate if you have used systemic corticosteroids or other immunosuppressive medications within 3 months prior to screening or if you intend to use them during screening.

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}

Is AGTC-501 safe for humans?

AGTC-501, also known as Laruparetigene zosaparvovec, has been tested in animals and humans. In animal studies, it was generally well tolerated with no significant safety concerns at lower doses, though higher doses showed some toxicity. In a human trial, the treatment was mostly safe, with some inflammation at higher doses that responded to steroids. ^{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 restoring the function of photoreceptors, the cells in the eye that detect light, potentially offering a more effective and long-lasting solution. ^{1 2 3 5 7}

Eligibility Criteria

This trial is for male subjects with a specific eye condition called X-linked Retinitis Pigmentosa, which must be caused by mutations in the RPGR gene. The eligibility criteria are not fully listed here, so additional requirements may apply.

Inclusion Criteria

Have a BCVA no better than 75 letters and no worse than 35 letters based on an ETDRS chart at each screening visit.

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

Have detectable baseline mean macular sensitivity measured by (MAIA) microperimetry, as determined by the investigator and confirmed by the Central Reading Center (CRC).

Exclusion Criteria

For subjects with herpes simplex virus (HSV):

Have a history of ocular herpes.

Have history of oral or genital herpes and unable and/or unwilling to utilize prophylactic antiviral medication.

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive a single dose of AGTC-501 in one eye, randomized to either a low or high dose group

Single occasion

Follow-up

Participants are monitored for safety and efficacy after receiving the treatment

12 months

Treatment Details

Interventions

• AGTC-501

Trial Overview The study is testing the safety and effectiveness of a gene therapy named rAAV2tYF-GRK1-RPGR on patients with X-linked Retinitis Pigmentosa due to RPGR mutations. It will compare two different doses of this treatment.

Participant Groups

Group I: Low Dose Group Experimental Treatment 1 Intervention

Male subjects at least 8 y/o treated with a lower dose (Dose 2 in RPGR-001 Horizon Phase 1/2 study) of rAAV2tYF-GRK1-RPGR study drug.

Group II: High Dose Group Experimental Treatment 1 Intervention

Male subjects at least 8 y/o treated with a higher dose (Dose 5 in RPGR-001 Horizon Phase 1/2 study) of rAAV2tYF-GRK1-RPGR study drug.

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]