Pipeline update: Catch up on recent breakthroughs in retinal therapies

The retina field continues to see significant developments in the FDA pipeline, with clinical trials advancing and receiving designations that may lead to approvals for treatments in wet and dry age-related macular degeneration (AMD), geographic atrophy (GA), diabetic macular edema (DME), and other retinal diseases.

4D-150

4D Molecular Therapeutics (4DMT) is advancing 4D-150, its treatment for wet AMD. In July 2025, the company announced an accelerated phase 3 development and a streamlined organization to drive late-stage execution.¹

The 4FRONT-1 trial (NCT06864988), the North American phase 3 clinical trial of 4D-150 in wet AMD, has exceeded initial projections for enrollment and site activation, the company stated in July.¹ Because of the program advancing ahead of its original timeline, 52-week topline data are now expected in the first half of 2027, rather than the second half. The 4FRONT-2 trial (NCT07064759), the second phase 3 trial of 4D-150, was initiated in June 2025, also ahead of schedule.¹ The 52-week topline data of 4FRONT-2 are expected in the second half of 2027.

“We are thrilled with the strong interest in 4D-150 from investigators and patients in both 4FRONT phase 3 studies, reflecting their belief in the phase 1/2 data demonstrating the tolerability and robust, durable clinical activity of this potential foundational backbone therapy for retinal vascular diseases,” Dhaval Desai, PharmD, chief development officer of 4DMT, said in a news release.

The company describes 4D-150 as “a potential backbone therapy that is designed to provide multiyear sustained delivery of anti-VEGF from the retina with a single, safe, intravitreal injection.”¹

The drug is also being investigated for the treatment of patients with DME.

4DMT presented positive 60-week results from the SPECTRA clinical trial (NCT05930561), which is evaluating 4D-150 in the treatment of DME.² SPECTRA is a prospective, multicenter, randomized, active-controlled, double-masked dose-ranging trial, which was conducted in 2 parts: dose confirmation and dose expansion.³ The data were presented by David R.P. Almeida, MD, PhD, MBA, president and CEO of Erie Retina Research in Pennsylvania, during the 2025 Annual American Society of Retina Specialists (ASRS) Scientific Meeting.

“The positive results from the SPECTRA trial demonstrate the tolerability and consistent, durable clinical activity of 4D-150 in DME, highlighting the potential for the product candidate to become a backbone therapy that can dramatically reduce treatment burden compared with the labeled regimen of standard-of-care aflibercept 2 mg every 8 weeks,” Almeida said in a news release.²

He added, “4D-150 has the potential to fundamentally transform the treatment of DME by reducing treatment burden with a product that has adherence by design, while providing meaningful, lasting vision improvement. This is especially important in DME, which frequently occurs in a working-age population.”

Highlights of the 60-week data include the following²:

1. 4D-150 was well-tolerated with no intraocular inflammation at any time point.
2. There were no reports of hypotony, endophthalmitis, vasculitis, choroidal effusions, or retinal artery occlusions.
3. Patient safety was maximized during the initial clinical assessment by using stringent supplemental aflibercept criteria.
4. Sustained gain of best corrected visual acuity (BCVA) of +9.7 letters was seen in the phase 3 dose.

In addition to the positive topline data, 4DMT also received the regenerative medicine advanced therapy (RMAT) designation from the FDA, and the next steps for approval are pending the final FDA and EMA alignment on a phase 3 clinical trial design and funding.²

AAVB-039

In August 2025, the FDA granted fast track designation to AAVantgarde Bio’s gene therapy program, AAVB-039, for the treatment of patients with Stargardt disease.⁴

“This designation represents an important milestone for our program and enables us to accelerate development efforts as we work to bring a potentially transformative therapy to patients as quickly as possible,” Natalia Misciattelli, PhD, chief executive officer of AAVantgarde, said in a news release.⁴

AAVB-039 aims to address the underlying cause of Stargardt disease secondary to biallelic mutation in ABCA4 by providing the full-length ABCA4 protein.⁴ The therapy’s safety, tolerability, and preliminary efficacy in patients with Stargardt disease is being evaluated in the phase 1/2 CELESTE (NCT07161544) clinical trial.⁴ Additionally, AAVantgarde is conducting a prospective natural history study, STELLA, across the US, Europe, and the United Kingdom (UK). STELLA has informed the clinical trial design of CELESTE.⁵

According to previous reporting from Ophthalmology Times, AAVantgarde also has its first clinical-stage product, AAVB-081, in phase 1/2 development for the treatment of retinitis pigmentosa.⁵

Ixo-vec ARTEMIS trial

Adverum Biotechnologies initiated the phase 3 ARTEMIS study in March 2025, with the screening completed in September 2025.^6,7

ARTEMIS (NCT06856577) is a US-based, multicenter, randomized, double-masked, active-comparator-controlled study evaluating a single intravitreal injection of ixoberogene soroparvovec (Ixo-vec) compared with an active comparator, in a broad participant population with neovascular (wet) AMD (nAMD).⁸

In this first of 2 planned phase 3 registrational trials, the primary end point is the mean change in BCVA of Ixo-vec (6 x 10¹⁰ vg/eye) compared with aflibercept (2 mg) every 8 weeks in both treatment-naive and previously treated patients, measured at weeks 52 and 56.^6-8 The second study, AQUARIUS, is expected to be conducted globally, with more details to come.⁶

“Leveraging our robust data for Ixo-vec, the ARTEMIS phase 3 trial was designed to enhance the potential for clinical, regulatory, and commercial success,” Rabia Gurses Ozden, MD, chief medical officer at Adverum, said in a news release.⁶ “We have been thrilled by the enthusiasm of retina specialists for this design, including studying Ixo-vec in both treatment-naïve and previously treated patients, which we expect will increase the speed of enrollment and generate a registrational dataset representative of real-world patient demographics.”

The company expects to complete enrollment of ARTEMIS of at least 284 treatment-naive and treatment-experienced patients in the fourth quarter of 2025, with a data readout expected in the first quarter of 2027.⁷

ANXV

Annexin Pharmaceuticals has received approval from the UK Medicines and Healthcare products Regulatory Agency (MHRA) to begin a clinical proof-of-concept phase 2a study for ANXV.⁹ ANXV is intended for the treatment of diabetic retinopathy (DR).

The company describes ANXV as “an investigational new drug containing the human protein Annexin A5, produced by the recombinant techniques in the bacteria Escherichia coli (E coli). Like endogenous Annexin A5, ANXV can protect cells, reduce adhesive properties, and influence the actions of immune cells.”¹⁰

In addition to patients with DR, patients with newly diagnosed retinal vein occlusion (RVO) will be included in preparation for an upcoming phase 2b study.⁹

Paulo-Eduardo Stanga, MD, will be the principal investigator of the phase 2a study, which will be conducted at The Retina Clinic in London, England.⁹ 

According to Annexin, the first patients are expected to be treated in the third quarter of 2025, with initial data expected approximately 3 months later and thereafter on an ongoing basis.⁹

“I have reviewed the phase 2a data in RVO (NCT05532735), and ANXV appears as a safe and promising drug candidate for the treatment of RVO and DR. I believe we will be able to further document safety and tolerability and capture potential early and beneficial effects in both diseases with the benefit of our clinical research experience and state-of-art functional and imaging equipment for assessing the retina,” Stanga said in a news release.⁹

Annexin previously concluded a phase 2a study on ANXV for the treatment of RVO, resulting in positive topline results.¹¹ The drug demonstrated a favorable safety profile, and the data support further clinical development of ANXV in RVO, the company said.¹¹

Vonaprument, formerly ANX007

In July 2025, Annexon announced the completion of its enrollment in the phase 3 ARCHER II trial (NCT06510816) of vonaprument (formerly ANX007) for the treatment of dry AMD with GA.¹²

The primary purpose of the study is to determine whether monthly intravitreal (IVT) injections of vonaprument reduce vision loss in participants with GA secondary to AMD.¹³

Granted fast track designation by the FDA, vonaprument is also the first therapeutic candidate for the treatment of GA to receive priority medicine (PRIME) designation in the European Union.¹¹

“The global reach of ARCHER II has increased awareness of vonaprument’s innovative mechanism and compelling phase 2 results,” David Eichenbaum, MD, FASRS, director of research at Retina Vitreous Associates of Florida, said in a news release. “With no approved therapies in Europe and limited options in the US, there is an urgent need for a treatment for GA that protects vision, the most clinically meaningful outcome for patients.”

Eichenbaum caught up with Modern Retina to talk about the ARCHER II study during the 2025 ASRS meeting.

Topline data from the phase 3 ARCHER II trial are expected in H2 2026.¹¹

Migaldendranib (MGB)

During the 2025 European Society of Retina Specialists Congress held in September in Paris, France, Ashvattha Therapeutics shared positive topline 40-week phase 2 data of MGB for the treatment of DME and nAMD.¹⁴

“These phase 2 results demonstrate the potential of MGB to address one of the biggest challenges in retinal care today: the treatment burden associated with frequent in-office intravitreal injections,” Susan Schneider, MD, acting chief medical officer of Ashvatta, said in a news release.

She added, “With the safe systemic and ocular outcomes seen to date, MGB offers a differentiated approach that has the possibility to enable monthly at-home subcutaneous administration and could meaningfully reduce the burden of care for patients with DME and nAMD, conditions that are chronic and typically bilateral.”

The key findings of the 40-week phase 2 clinical trial include the following¹⁵:

• The annualized rate of IVT injections in all study eyes (DME and nAMD) decreased from 8.4 to 1.6 per year, or a 78.6% (4.7-fold) DME (n=8) and an 83.4% (6-fold) nAMD (n=14) reduction in the need for supplemental anti-VEGF vs prestudy IVT injections.
• A bilateral MGB treatment benefit was demonstrated with the annualized rate of IVT injections in all fellow eyes, decreasing from 8.3 to 0.6 per year, or an 89.1% (9.1-fold) reduction in the need for supplemental anti-VEGF vs prestudy IVT injections.
• The mean change from baseline to week 40 was +6.1 ETDRS letters in BCVA and –23.3 μm in central subfield thickness (CST) in DME study eyes.
• Improvements in BCVA and CST were also observed in nAMD study eyes.
• Subcutaneous MGB is safe and well-tolerated, with no treatment-related systemic or ocular serious adverse events reported, and no clinically significant changes from baseline in renal, hepatic, or cardiac values.

Laru-zova

During this busy conference season, Beacon Therapeutics shared positive topline data for 2 of the company’s phase 2 trials: SKYLINE (NCT06333249) and DAWN (NCT06275620), both investigating laruparetigene zovaparvovec (laru-zova) for the treatment of X-linked retinitis pigmentosa (XLRP).¹⁶

The data showed that laru-zova was well-tolerated by SKYLINE participants through month 36, and DAWN patients at month 9 or longer.¹⁶

Currently, laru-zova has RMAT and fast track designations from the FDA, PRIME designation from the European Medicines Agency (EMA), innovative licensing and access pathway from the MHRA, as well as orphan drug designation from both the FDA and EMA.¹⁷

“We are pleased to be sharing key data from our DAWN and SKYLINE trials, building on one of the most significant bodies of evidence for a gene therapy in ocular disease,” Daniele Chung, DO, MA, chief medical officer of Beacon Therapeutics, said in a news release.¹⁷ “These new data updates reinforce our belief in the potential for laru-zova through clinical development while engaging with regulators and the patient community.”

Additionally, low-luminance visual acuity is being evaluated as the primary end point in Beacon’s ongoing pivotal phase 2/3 VISTA trial (NCT04850118) of laru-zova for the treatment of XLRP.¹⁷ The company completed enrollment of VISTA in July 2025 and expects to report topline data in the second half of 2026.¹⁷

Beacon plans to support its regulatory submissions to the US and Europe with the data from the VISTA trial alongside long-term data from the ongoing phase 2 DAWN, phase 1/2 HORIZON, and phase 2 SKYLINE studies.¹⁸

“The VISTA study has been carefully designed to provide the clinical evidence needed to demonstrate laru-zova’s potential to improve functional vision in patients with XLRP,” Chung said in a news release.¹⁸ “We are applying our deep understanding of both ocular disease and gene therapy by using a highly efficient AAV capsid and a stabilized gene cassette that expresses the full-length RPGR protein, to support better vision outcomes.”

Modern Retina covers the latest in FDA news. Stay tuned for more updates as they become available.

References

1. 4DMT announces accelerated 4D-150 phase 3 development in wet AMD and streamlined organization to drive late-stage execution. 4D Molecular Therapeutics. July 2, 2025. Accessed October 13, 2025. https://4dmt.gcs-web.com/news-releases/news-release-details/4dmt-announces-accelerated-4d-150-phase-3-development-wet-amd

2. 4DMT presents positive 60-week results from 4D-150 SPECTRA clinical trial in DME and regulatory update. 4D Molecular Therapeutics. July 31, 2025. Accessed October 13, 2025. https://ir.4dmoleculartherapeutics.com/news-releases/news-release-details/4dmt-presents-positive-60-week-results-4d-150-spectra-clinical

3. 4D-150 in patients with diabetic macular edema. Clinicaltrials.gov. Updated September 22, 2025. Accessed October 13, 2025. https://clinicaltrials.gov/study/NCT05930561?term=4D-150&rank=1

4. AAVantgarde Bio announces FDA fast track designation for AAVB-039 for the treatment of Stargardt disease. AAVantgarde. August 12, 2025. Accessed October 13, 2025. https://www.aavantgarde.com/en/news/aavantgarde-bio-announces-fda-fast-track-designation-for-aavb-039-for-the-treatment-of-stargardt-disease/ 

5. Harp MD. FDA grants fast track designation to AAVantgarde Bio for AAVB-039. Ophthalmologytimes.com. August 12, 2025. Accessed October 13, 2025. https://www.ophthalmologytimes.com/view/fda-grants-fast-track-designation-to-aavantgarde-bio-for-aavb-039

6. Adverum Biotechnologies initiates ARTEMIS phase 3 study evaluating Ixo-vec for wet AMD. Adverum.com. March 3, 2025. Accessed October 13, 2025. https://investors.adverum.com/press_releases/news-details/2025/Adverum-Biotechnologies-Initiates-ARTEMIS-Phase-3-Study-Evaluating-Ixo-vecfor-Wet-AMD/default.aspx

7. Adverum Biotechnologies announces completion of screening for pivotal phase 3 ARTEMIS trial of Ixo-vec for wet age-related macular degeneration. Adverum.com. September 22, 2025. Accessed October 13, 2025. https://investors.adverum.com/press_releases/news-details/2025/Adverum-Biotechnologies-Announces-Completion-of-Screening-for-Pivotal-Phase-3-ARTEMIS-Trial-of-Ixo-vec-for-Wet-Age-Related-Macular-Degeneration/default.aspx

8. Efficacy and safety study of ixoberogene soroparvovec (ixo-vec) in participants with neovascular age-related macular degeneration (ARTEMIS). Clinicaltrials.gov. Updated October 2, 2025. Accessed October 13, 2025. https://clinicaltrials.gov/study/NCT06856577?term=ARTEMIS%20IXO-VEC&rank=1

9. Annexin receives approval for phase 2a study in diabetic retinopathy and RVO. Annexin Pharmaceuticals EN. August 27, 2025. Accessed October 13, 2025. https://annexinpharma.com/mfn_news/annexin-receives-approval-for-phase-2a-study-in-diabetic-retinopathy-and-rvo/

10. ANXV. Annexin Pharmaceuticals EN. Accessed October 13, 2025. https://annexinpharma.com/anxv/

11. Annexin reports promising topline results in RVO phase 2a study. Annexin Pharmaceuticals EN. August 21, 2024. Accessed October 13, 2025. https://annexinpharma.com/mfn_news/annexin-reports-promising-topline-results-in-rvo-phase-2a-study/

12. Harp MD. Annexon completes enrollment in phase 3 ARCHER II trial of vonaprument for geographic atrophy. Ophthalmology Times. July 24, 2025. Accessed October 13, 2025. https://www.ophthalmologytimes.com/view/annexon-completes-enrollment-in-phase-3-archer-ii-trial-of-vonaprument-for-geographic-atrophy

13. A study investigating the efficacy and safety of intravitreal (IVT) injections of ANX007 in participants with geographic atrophy (GA) (ARCHER II). Clinicaltrials.gov. Updated May 11, 2025. Accessed October 13, 2025. https://clinicaltrials.gov/study/NCT06510816

14. Hennings D. Ashvattha Therapeutics announces positive topline 40-week phase 2 results for migaldendranib in diabetic macular edema and neovascular age-related macular degeneration. Ashvattha Therapeutics. September 4, 2025. Accessed October 13, 2025. https://avttx.com/ashvattha-therapeutics-announces-positive-topline-40-week-phase-2-results-for-migaldendranib-in-diabetic-macular-edema-and-neovascular-age-related-macular-degeneration/

15. Filkins K. Ashvattha reports positive phase 2 results for migaldendranib in DME and nAMD. Ophthalmologytimes.com. September 5, 2025. Accessed October 13, 2025. https://www.ophthalmologytimes.com/view/ashvattha-reports-positive-phase-2-results-for-migaldendranib-in-dme-and-namd

16. Filkins K. Beacon Therapeutics announces positive topline data from DAWN and SKYLINE trials. Modern Retina. September 8, 2025. Accessed October 13, 2025. https://www.modernretina.com/view/beacon-therapeutics-announces-positive-topline-data-from-dawn-and-skyline-trials

17. Beacon Therapeutics announces positive interim 9+ month results from DAWN trial and 36-month phase 2 SKYLINE trial data for laru-zova in patients with X-linked retinitis pigmentosa (XLRP) at EURETINA 2025. Beacon Therapeutics. September 4, 2025. Accessed October 13, 2025. https://www.beacontx.com/news-and-events/beacon-therapeutics-announces-positive-interim-9-month-results-fromdawn-trial-and-36-month-phase-2-skyline-trial-data-for-laru-zova-in-patients/

18. Beacon Therapeutics completes enrollment in registrational phase 2/3 VISTA trial of laru-zova for patients with XLRP. Beacon Therapeutics. July 8, 2025. Accessed October 13, 2025. https://www.beacontx.com/news-and-events/beacon-therapeutics-completes-enrollment-in-registrational-phase-2-3-vista-trial-of-laru-zova-for-patients-with-xlrp/