A Phase I/II Dose-escalation and Dose-expansion Study to Evaluate the Safety and Efficacy of FT-002 Subretinal Injection in Subjects With RPGR Gene Mutation-associated X-linked Retinitis Pigmentosa.

The aim of this study was to evaluate the safety, tolerability, and efficacy of one-time subretinal injection of FT-002 in male subjects (8-45 years of age) with RPGR (Retinitis Pigmentosa GTPase Regulator) gene mutation-associated X-linked retinitis pigmentosa, of XLRP. This study includes Phase I (dose escalation phase) and Phase II (dose expansion phase).

Start Date01 Apr 2024

Sponsor / Collaborator

Frontera Therapeutics, Inc.Startup

NCT04850118 / RecruitingPhase 2/3

A Randomized, Controlled, Masked, Multi-center Study Evaluating the Efficacy, Safety, and Tolerability of Two Doses of AGTC-501 Compared to an Untreated Control Group in Male Participants With X-linked Retinitis Pigmentosa

This study will evaluate and compare the safety, efficacy, and tolerability of 2 doses of a recombinant adeno-associated virus vector (AGTC-501) to an untreated control group in male participants with X-linked retinitis pigmentosa caused by RPGR mutations.

Start Date14 Mar 2024

Sponsor / Collaborator

Beacon Therapeutics (USA), Inc.

NCT06275620 / Enrolling by invitationPhase 2

A Phase 1/2 Open-Label Dose Escalation Study to Evaluate the Safety and Efficacy of AGTC-501 (rAAV2tYF-GRK1-RPGR) and a Phase 2 Randomized, Controlled, Masked, Multi-center Study Comparing Two Doses of AGTC-501 in Male Participants With X-linked Retinitis Pigmentosa

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.

Start Date14 Nov 2023

Sponsor / Collaborator

Beacon Therapeutics (USA), Inc.

100 Clinical Results associated with RPGR

100 Translational Medicine associated with RPGR

0 Patents (Medical) associated with RPGR

541

Literatures (Medical) associated with RPGR

01 Nov 2024·AMERICAN JOURNAL OF OPHTHALMOLOGY

Phase 1/2 AAV5-hRKp.RPGR (Botaretigene Sparoparvovec) Gene Therapy: Safety and Efficacy in RPGR-Associated X-Linked Retinitis Pigmentosa

Article

Author: Minnick, Pansy ; Georgiadis, Anastasios ; Fleck, Penny R ; Kumaran, Neruban ; Tee, James J L ; Smith, Alexander J ; Bainbridge, James ; Michaelides, Michel ; Kalitzeos, Angelos ; Xu, Jialin ; Georgiou, Michalis ; Yang, Yesa ; DE Guimaraes, Thales A C ; Besirli, Cagri G ; Ali, Robin R ; Comander, Jason I ; Huckfeldt, Rachel M ; Ripamonti, Caterina ; Shah, Syed Mahmood ; Wong, Peggy ; Forbes, Alexandria ; Fung, Albert ; Peluso, Colleen ; Anglade, Eddy ; Naylor, Stuart ; Wong, Sui Chien ; Sahel, José-Alain ; Zeldin, Robert ; Clark, Michael

PURPOSE:

To assess the safety and efficacy of AAV5-hRKp.RPGR in participants with retinitis pigmentosa GTPase regulator (RPGR)-associated X-linked retinitis pigmentosa (XLRP).

DESIGN:

Open-label, phase 1/2 dose escalation/expansion study (ClinicalTrials.gov Identifier: NCT03252847).

METHODS:

Males (≥5 years old) with XLRP-RPGR were evaluated. In the dose escalation phase, subretinal AAV5-hRKp.RPGR (low: 1.0 × 10¹¹ vg/ml; intermediate: 2.0 × 10¹¹ vg/ml; high: 4.0 × 10¹¹ vg/ml) was administered to the poorer-seeing eye (n = 10). Dose confirmation (intermediate dose) was carried out in 3 pediatric participants. In the dose expansion phase, 36 participants were randomized 1:1:1 to immediate (low or intermediate dose) or deferred (control) treatment. The primary outcome was safety. Secondary efficacy outcomes included static perimetry, microperimetry, vision-guided mobility, best corrected visual acuity, and contrast sensitivity. Safety and efficacy outcomes were assessed for 52 weeks for immediate treatment participants and 26 weeks for control participants.

RESULTS:

AAV5-hRKp.RPGR was safe and well tolerated, with no reported dose-limiting events. Most adverse events (AEs) were transient and related to the surgical procedure, resolving without intervention. Two serious AEs were reported with immediate treatment (retinal detachment, uveitis). A third serious AE (increased intraocular pressure) was reported outside the reporting period. All ocular inflammation-related AEs responded to corticosteroids. Treatment with AAV5-hRKp.RPGR resulted in improvements in retinal sensitivity and functional vision compared with the deferred group at Week 26; similar trends were observed at Week 52.

CONCLUSIONS:

AAV5-hRKp.RPGR demonstrated an anticipated and manageable AE profile through 52 weeks. Safety and efficacy findings support investigation in a phase 3 trial.

01 Oct 2024·Canadian journal of ophthalmology. Journal canadien d'ophtalmologie

Molecular genetic diagnostics for inherited retinal dystrophies in the clinical setting

Article

Author: Gregory-Evans, Kevin ; Huang, Albert ; Kolawole, Olubayo U ; Shunmugam, Maheshver ; Weaver, Travers ; Gregory-Evans, Cheryl Y

OBJECTIVE:

To evaluate the success of diagnostic genetic testing in inherited retinal dystrophy (IRD) patients in the clinical setting.

DESIGN:

Retrospective cohort analysis.

PARTICIPANTS:

A total of 446 consecutive participants from diverse ethnic backgrounds living in western Canada.

METHODS:

Clinical information was collected from participants, including family history, and they underwent a full ophthalmic examination with chart review. Those with a suspected IRD were offered panel-based genetic testing of 351 genes between March 1, 2019, and February 28, 2022. The main outcome measure was effect of the genetic testing results on clinical diagnosis.

RESULTS:

Genetic testing established a conclusive molecular diagnosis in 249 of 446 cases (55.8%), a clearly negative result in 90 of 446 cases (20.1%), and an inconclusive diagnosis in 108 of 446 cases (24.2%). Conclusive disease-causing variants were identified in 69 genes, and the most commonly affected genes were ABCA4 (31 variants), USH2A (25 variants), and RPGR (19 variants). The inconclusive group included likely novel autosomal dominant variants or a pathogenic variant with a variant of uncertain significance in the same gene for a recessive phenotype. Notably, an inconclusive molecular genetic diagnosis was seen in as many as 47.3% of East Asian participants with an outer retinal dystrophy.

CONCLUSIONS:

This study represents the largest review of molecular genetic testing in IRDs in Canada. That negative or inconclusive results obtained in approximately 45% of cases demonstrates that there is an important need for new research into molecular genetic causes of IRDs. This is particularly true in addressing the problem of interpreting a variant of uncertain significance in ethnic minorities.

17 Sep 2024·Translational Vision Science & Technology

Establishing Clinical Trial Endpoints in Selecting Patients for RPGR Retinal Gene Therapy

Article

Author: Cehajic-Kapetanovic, Jasmina ; MacLaren, Robert E. ; Josan, Amandeep S. ; Christou, Evita Evangelia

Purpose:

Clinical trials for X-linked retinitis pigmentosa (RP) often assess retinal structure using optical coherence tomography (OCT) and function using microperimetry to evaluate initial eligibility and endpoints. Therefore, we seek to determine which parameters might be most sensitive in screening new patients for enrollment.

Methods:

Thirty-one patients (62 eyes) with confirmed retinitis pigmentosa GTPase regulator (RPGR) mutations attending Oxford Eye Hospital were included in this retrospective analysis. Outer retinal structure was investigated by measuring the remaining ellipsoid zone (EZ) and external limiting membrane (ELM) on OCT. Visual function was evaluated by using 10-2 microperimetry mean sensitivity.

Results:

The median age of patients with RPGR was 31 years (interquartile range [IQR] = 22-39 years). For the right and left eyes, respectively, the median EZ length through the foveal section was 921 µm (IQR = 607-1570) and 865 µm (IQR = 508-1442) and median ELM length was 2056 µm (IQR = 1336-2764) and 1860 µm (IQR = 1152-2680). Similarly, the median microperimetry sensitivity (MS) was 2.0 decibel (dB; IQR = 0.4-5.4) and 1.1 dB (IQR = 0.1-5.4). Linear mixed model regression analysis showed that EZ was significantly positively correlated to ELM (P < 0.001, R² = 0.931). EZ and ELM were significantly correlated with the microperimetry sensitivity with exponential relationship (P < 0.001, R² = 0.71 and 0.72, respectively). Using the exponential equation of regression line, EZ below approximately 600 µm (RE = 637 µm, 95% confidence interval [CI] = 397-877, LE = 586 µm, 95% CI = 356-817) results in microperimetry sensitivity of approximately 0 dB. There was high degree of inter-eye symmetry for progression of EZ, ELM, and microperimetry sensitivity. Age was significantly correlated with the analyzed parameters (P < 0.001), although with low R² for each of them.

Discussion:

EZ may comprise a surrogate biomarker for prediction of visual function in X-linked RP caused by mutations in RPGR and, in turn, identification of appropriate patients for enrollment in clinical trials. As expected, age plays a role in predicting potential biomarkers and visual function, however, it should not be used to preclude patients for gene therapy due to the poor correlation and heterogeneity of disease onset.

Translational Relevance:

Biomarkers of visual function in RPGR-associated RP may lead to identification of appropriate patients for enrollment in clinical trials.

News (Medical) associated with RPGR

19 Sep 2024

·www.prnewswire.com

Beacon Therapeutics Presents 36-Month Interim Results from Phase I/2 HORIZON Trial of AGTC-501 in Patients with XLRP

LONDON and CAMBRIDGE, Mass., Sept. 19, 2024 /PRNewswire/ -- Beacon Therapeutics Holdings Limited ('Beacon' or 'the Company'), a leading ophthalmic gene therapy company with a purpose to save and restore the vision of patients with blinding retinal diseases, today presented 36-month interim results from its Phase I/2 HORIZON trial of its lead asset, AGTC-501, in patients with X-linked retinitis pigmentosa (XLRP) at the 24th EURETINA Congress held in Barcelona, Spain. Key presentation highlights included: AGTC-501 was reported to be generally safe and well-tolerated in the 29 patients enrolled with no clinically significant safety events related to the therapy. Data also demonstrated that a difference in visual function between the treated and untreated eyes was still observed at month 36. The benefit-risk profile of AGTC-501 supports ongoing clinical development for the treatment of patients with XLRP caused by RPGR mutations. Lance Baldo, MD, Chief Executive Officer of Beacon, stated, "This emerging longer-term data is another clinical validation of the safety of AGTC-501 for the treatment of XLRP. We look forward to achieving several upcoming clinical milestones, including 24-month data from the Phase 2 SKYLINE trial in XLRP later this year, and continued enrollment into our open-label Phase 2 DAWN trial and Phase 2/3 VISTA trial." HORIZON is a Phase 1/2, open-label, dose-escalation study of patients with XLRP treated with subretinal AGTC-501, which has completed enrollment of 29 male participants and all participants are in long-term follow-up. Presentation – Subretinal Gene Therapy Drug AGTC-501 for X-Linked Retinitis Pigmentosa (XLRP) Phase 1/2 Multicenter Study (HORIZON): 36-Month Interim Results Presenter – Paul Yang, MD, PhD, Chief, Paul H. Casey Ophthalmic Genetics Division, Casey Eye Institute, OHSU The presentation took place on Thursday, September 19th at 15:30 CEST. About Beacon Therapeutics Beacon Therapeutics is an ophthalmic gene therapy company founded in 2023 to save and restore the vision of patients with a range of prevalent and rare retinal diseases that result in blindness. The Company has an established scientific foundation that combines a late-stage development candidate to treat X-linked retinitis pigmentosa (XLRP), as well as two preclinical programs, one targeting dry age-related macular degeneration (AMD) and another targeting cone-rod dystrophy (CRD). Beacon Therapeutics also has access to a target generation technology platform that will identify, screen, and search secreted proteins in the ophthalmology space. Lead development candidate AGTC-501, is a gene therapy program currently being investigated for the treatment of XLRP, an inherited monogenic recessive disorder that causes progressive vision loss, primarily in boys and young men. XLRP is predominantly caused by mutations in the retinitis pigmentosa GTPase regulator (RPGR) gene. AGTC-501 expresses the full length RPGR protein, thereby addressing the full complement of photoreceptor damage caused by XLRP, including both rod and cone loss. Beacon is supported by funds from Syncona Limited, Forbion, Oxford Science Enterprises, TCGX, Advent Life Sciences and additional investors. Find out more about Beacon Therapeutics at beacontx.com. Contact: [email protected] Media: [email protected] SOURCE Beacon Therapeutics WANT YOUR COMPANY'S NEWS FEATURED ON PRNEWSWIRE.COM? 440k+ Newsrooms & Influencers 9k+ Digital Media Outlets 270k+ Journalists Opted In GET STARTED

Clinical ResultGene TherapyPhase 2

03 Jul 2024

·www.prnewswire.com

Beacon Therapeutics Raises $170 Million in Series B Funding to Advance Development of Ophthalmic Gene Therapies

Financing led by life sciences venture capital firm Forbion, alongside existing investors Syncona and Oxford Science Enterprises, as well as new investors TCGX and Advent Life Sciences Round will accelerate the development of lead asset AGTC-501 and broader pipeline Beacon appoints Dmitrij Hristodorov, Wouter Joustra, and Cariad Chester to Board of Directors; Dominic Schmidt joins as a Board Observer LONDON and CAMBRIDGE, Mass., July 3, 2024 /PRNewswire/ -- Beacon Therapeutics Holdings Limited ('Beacon Therapeutics' or 'the Company'), a leading ophthalmic gene therapy company with a mission to save and restore the vision of patients with blinding retinal diseases, today announced it has raised $170 million in Series B funding. Forbion led the financing, which included existing investors Syncona Limited, Oxford Science Enterprises and the University of Oxford, as well as initial investments from TCGX and Advent Life Sciences. The funds will be used to support the continued clinical development of Beacon's lead asset, AGTC-501 for X-Linked Retinitis Pigmentosa (XLRP) and generate Phase 1/2 clinical trial data for the Company's Dry Age-related Macular Degeneration (dAMD) program. Beacon Therapeutics also appointed Dmitrij Hristodorov and Wouter Joustra, General Partners of Forbion, and Cariad Chester, Managing Partner of TCGX, to its Board of Directors. Dominic Schmidt, General Partner of Advent Life Sciences, joins as a Board Observer. Beacon is focused on both orphan and prevalent diseases, including XLRP, a blinding orphan disease for which there is no available treatment, as well as dAMD. AGTC-501, the Company's lead asset, is currently in a registrational clinical trial for the treatment of XLRP. AGTC-501 expresses the full length RPGR protein, thereby addressing all photoreceptor damage caused by XLRP, including both rod and cone loss. David Fellows, Chief Executive Officer of Beacon Therapeutics, said, "We are focused on progressing our pipeline of ophthalmic gene therapies to save and restore the vision of patients with a range of prevalent and rare retinal diseases that result in blindness. I am confident that along with the addition of Dmitrij Hristodorov, Wouter Joustra and Cariad Chester to the Beacon Board, these funds will support the ongoing development of our late-stage and pre-clinical pipeline and enable acceleration of the development of AGTC-501 as we progress through the clinic and toward commercialization." "Forbion is pleased to support Beacon Therapeutics at this critical juncture in the development of its pipeline of pioneering ophthalmic gene therapies. Beacon's deep expertise and renowned management bench give us confidence in the plan to build a leading retinal gene therapy company," shared Dmitrij Hristodorov, General Partner at Forbion. Elisa Petris, Lead Partner at Syncona Investment Management Limited and Board Director of Beacon Therapeutics, said, "Syncona's continued backing of Beacon Therapeutics is a testament to the Company's proven leadership team and innovative approach to developing gene therapies for retinal diseases. This financing and the partnership of this high-quality syndicate will propel Beacon's pipeline and enable the Company to advance its programs for both rare and prevalent ophthalmic diseases." Beacon has raised approximately $290 million in funding to date. This funding round follows several clinical milestones for the company, including the first patient dosed in the VISTA registrational trial for AGTC-501, the initiation of the Phase II DAWN trial and the presentation of positive 12-month interim results of the Phase 2 SKYLINE trial at the 47th Annual Macula Society Meeting demonstrating the precision, effectiveness and safety of Beacon's therapeutic interventions. J.P. Morgan acted as sole placement agent to Beacon Therapeutics for this transaction. About Beacon Therapeutics Beacon Therapeutics is an ophthalmic gene therapy company founded in 2023 to save and restore the vision of patients with a range of prevalent and rare retinal diseases that result in blindness. The Company has an established scientific foundation that combines a late-stage development candidate to treat X-linked retinitis pigmentosa (XLRP), as well as two preclinical programs, one targeting dry age-related macular degeneration (AMD) and another targeting cone-rod dystrophy (CRD), an inherited retinal disease. Lead development candidate AGTC-501, is a gene therapy program currently being investigated for the treatment of XLRP, an inherited monogenic recessive disorder that causes progressive vision loss in boys and young men. XLRP is predominantly caused by mutations in the retinitis pigmentosa GTPase regulator (RPGR) gene. AGTC-501 expresses the full length RPGR protein, thereby addressing the full complement of photoreceptor damage caused by XLRP, including both rod and cone loss. Beacon Therapeutics also has access to a target generation technology platform that will identify, screen, and search secreted proteins in the ophthalmology space. Find out more about Beacon Therapeutics at beacontx.com. Contact: [email protected] Media: [email protected] SOURCE Beacon Therapeutics

Phase 2Executive ChangeGene Therapy

03 Jul 2024

·www.fiercebiotech.com

Beacon attracts $170M series B to push eye disease gene therapy through late-stage trial

Beacon Therapeutics said it would use part of its $170 million haul to generate a phase 1/2 trial for its dry age-related macular degeneration program. Beacon Therapeutics has raised a $170 million series B, which the U.K.-based gene therapy biotech will use to push its eye disease candidates through clinical trials. London-based Beacon (which also has a base in Massachusetts) launched with $120 million back in 2023 and came with a mission to develop a new generation of gene therapies for retinal diseases that cause blindness. The latest funding round takes the total amount the biotech has so far drawn into a meaty $290 million. European life-sciences-focused growth fund Forbion led the round, while London-based VC firm Syncona and Oxford Science Enterprises both returned. There were also initial investments from TCGX and Advent Life Sciences. Beacon said it would use the latest funds to continue to develop its lead asset AGTC-501, which is currently in a phase 2/3 clinical trial for the treatment of X-linked retinitis pigmentosa (XLRP). The asset was acquired by Syncona as part of its buyout of Applied Genetic Technologies Corporation in 2022. The first patient was dosed in the XLRP study last month. The plan is to combine the results with data from a phase 1/2 trial and a phase 2 study in the same indication to support applications for approval in the U.S. and Europe. “Unlike other approaches in the space, AGTC-501 expresses the full-length RPGR protein, thereby addressing all photoreceptor damage caused by XLRP, including both rod and cone loss,” Beacon explained in the July 3 release. The U.K. biotech also said it would use part of the $170 million haul to generate a phase 1/2 trial for its dry age-related macular degeneration program. As part of the financing, Beacon added to its board in the form of Forbion general partners Dmitrij Hristodorov, Ph.D., and Wouter Joustra alongside TCGX Managing Partner Cariad Chester. “We are focused on progressing our pipeline of ophthalmic gene therapies to save and restore the vision of patients with a range of prevalent and rare retinal diseases that result in blindness,” Beacon CEO David Fellows said in the release. “I am confident that along with the addition of Dmitrij Hristodorov, Wouter Joustra and Cariad Chester to the Beacon Board, these funds will support the ongoing development of our late-stage and preclinical pipeline and enable acceleration of the development of AGTC-501 as we progress through the clinic and toward commercialization,” Fellows added. Elisa Petris, lead partner at Syncona and board director of Beacon, said the investment firm’s “continued backing of Beacon Therapeutics is a testament to the company’s proven leadership team and innovative approach to developing gene therapies for retinal diseases.” “This financing and the partnership of this high-quality syndicate will propel Beacon’s pipeline and enable the company to advance its programs for both rare and prevalent ophthalmic diseases,” Petris added.

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