MedPath

AAV2sFLT01 (Applied Genetic Technologies/Genzyme) Advanced Drug Monograph

Published:May 29, 2025

AAV2-sFLT01: An Investigational Gene Therapy for Ocular Neovascularization

1. Introduction to AAV2-sFLT01

1.1. Overview of AAV2-sFLT01 as an Investigational Gene Therapy

AAV2-sFLT01 is an investigational gene therapy product that was developed to address ocular diseases characterized by abnormal blood vessel growth (neovascularization). The therapeutic agent consists of a recombinant, replication-defective adeno-associated virus serotype 2 (AAV2) vector.[1] AAV vectors are a common choice in gene therapy due to their ability to transduce a variety of cell types, including the non-dividing cells of the retina, and their generally favorable safety profile, which includes a lack of known human pathogenicity and a tendency for the delivered genetic material to remain episomal (not integrating into the host genome).[1] The AAV2-sFLT01 vector is engineered to carry and express the sFLT01 gene, which codes for a soluble anti-angiogenic protein.[1] The primary route of administration investigated for AAV2-sFLT01 was intravitreal (IVT) injection, a common and minimally invasive method for delivering therapeutics directly into the vitreous cavity of the eye, allowing the agent to diffuse and reach target tissues in the posterior segment.[1]

1.2. Therapeutic Rationale: Targeting Vascular Endothelial Growth Factor (VEGF)

The therapeutic strategy underlying AAV2-sFLT01 centers on the inhibition of Vascular Endothelial Growth Factor (VEGF), particularly VEGF-A. VEGF-A is a potent signaling protein that plays a crucial role in stimulating angiogenesis and increasing vascular permeability. These processes are key pathological drivers in several common and severe ocular diseases.[1]

Current standard-of-care treatments for conditions such as neovascular (wet) Age-Related Macular Degeneration (nAMD) involve the repeated intravitreal administration of anti-VEGF proteins, such as ranibizumab, aflibercept, and bevacizumab. While these therapies have significantly improved visual outcomes for many patients, they necessitate frequent injections, often on a monthly or bimonthly basis, over extended periods. This high treatment frequency imposes a considerable burden on patients, their families, and healthcare systems, and also carries cumulative risks associated with repeated intraocular procedures, such as endophthalmitis, retinal detachment, and intraocular hemorrhage.[6]

The development of AAV2-sFLT01 was a strategic response to this significant unmet medical need. The core rationale was to establish a long-term, self-regulating intraocular "biofactory" where the patient's own retinal cells, once transduced by the AAV2 vector, would continuously produce and secrete the therapeutic sFLT01 anti-VEGF protein. A single administration of the gene therapy was intended to achieve sustained therapeutic protein levels within the eye, thereby potentially reducing or even eliminating the need for frequent follow-up protein injections and alleviating the associated treatment burden.[1] This approach is representative of a broader trend in ophthalmology aimed at developing more durable treatment solutions for chronic retinal diseases.

1.3. Intended Indications

The primary therapeutic target for AAV2-sFLT01 was neovascular (wet) Age-Related Macular Degeneration (nAMD). This indication was the focus of the Phase 1 clinical trial program.[1] nAMD is a leading cause of severe and irreversible vision loss in individuals aged 60 and older in many parts of the world. It is characterized by the abnormal growth of new blood vessels from the choroid (choroidal neovascularization, CNV) that extend beneath or into the neurosensory retina. These new vessels are fragile and prone to leakage, leading to the accumulation of subretinal and intraretinal fluid, hemorrhage, and ultimately, damage to photoreceptors and the retinal pigment epithelium (RPE), resulting in central vision loss.[6]

AAV2-sFLT01 was also investigated for the treatment of diabetic retinopathy.[15] Diabetic retinopathy is a common microvascular complication of diabetes mellitus and a significant cause of vision loss in working-age adults. Proliferative diabetic retinopathy, an advanced stage, is also characterized by neovascularization that can lead to vitreous hemorrhage and tractional retinal detachment.[10] However, the development of AAV2-sFLT01 for diabetic retinopathy was subsequently discontinued.[15] The underlying technology also held potential for treating other ocular diseases driven by pathological neovascularization.[7]

1.4. Alternative Names and Code Designations

Throughout its development, AAV2-sFLT01 has been referred to by several names and codes:

  • GZ-402663: This was the internal code designation used by Genzyme Corporation (later Sanofi) during the clinical development of the product.[14]
  • sFLT-01 or sFLT01: These terms are commonly used to refer to the soluble Flt-1 protein encoded by the transgene, and sometimes by extension, to the vector expressing this protein.[1]
  • Some pharmaceutical databases also list "age-related macular degeneration gene therapy - Beacon Therapeutics" and "anti vascular endothelial growth factor (VEGF) gene therapy - Beacon Therapeutics" as alternative names or synonyms.[15] However, as will be discussed in Section 3, Beacon Therapeutics' current active development pipeline does not appear to include AAV2-sFLT01, suggesting these listings may reflect historical associations or database lag following corporate acquisitions. The complexities in developer attribution highlight the dynamic nature of pharmaceutical asset management.

The design of sFLT01 as a modified soluble form of VEGF receptor 1, rather than an antibody fragment like ranibizumab, was an early attempt to create a broad-spectrum "VEGF trap." This approach aimed to neutralize multiple VEGF isoforms and potentially Placental Growth Factor (PlGF), similar to the mechanism of aflibercept, suggesting a therapeutic design philosophy beyond simple VEGF-A neutralization.[1] This indicates an evolution in thinking towards more comprehensive anti-angiogenic strategies within the gene therapy framework.

2. Mechanism of Action

2.1. The sFLT01 Transgene: Design and Function

The therapeutic component of AAV2-sFLT01 is the sFLT01 transgene, which encodes a soluble, chimeric anti-angiogenic protein.

  • Molecular Composition: sFLT01 is engineered by fusing domain 2 of the human VEGF receptor 1 (VEGFR-1), also known as Fms-like tyrosine kinase 1 (Flt-1), to the Fc portion (specifically the CH2 and CH3 domains) of human Immunoglobulin G1 (IgG1).[1] Domain 2 of VEGFR-1 contains a high-affinity binding site for VEGF-A. The IgG1 Fc fragment is often included in therapeutic fusion proteins to enhance stability during production and purification, and potentially to extend in vivo half-life, although the latter is less critical for a protein that is continuously expressed by a gene therapy vector within a localized compartment like the eye. Some descriptions also mention a polyglycine linker connecting the hVEGFR1/Flt-1 domain 2 to the Fc region, which can provide flexibility and proper folding of the fusion protein.[8]
  • Promoter System: The expression of the sFLT01 gene within the AAV2 vector is driven by a strong, constitutive promoter, typically the chicken β-actin (CBA) promoter, often used in conjunction with a cytomegalovirus (CMV) enhancer. This combination is chosen to ensure robust and sustained transgene expression in the transduced ocular cells.[1]
  • Anti-Angiogenic Function: Once synthesized and secreted by the transduced cells, sFLT01 acts as a potent "VEGF trap" or "decoy receptor." It circulates within the intraocular environment and binds with high affinity to free VEGF-A, sequestering it.[1] By binding VEGF-A, sFLT01 prevents this critical angiogenic factor from interacting with its natural cellular receptors (VEGFR-1 and VEGFR-2) located on the surface of vascular endothelial cells. This blockade inhibits the downstream signaling pathways that promote endothelial cell proliferation, migration, survival, and new blood vessel formation.[8] Furthermore, sFLT01 may also bind and neutralize Placental Growth Factor (PlGF), another pro-angiogenic factor implicated in ocular neovascularization.[8] This potential dual-targeting capability could offer a broader spectrum of anti-angiogenic activity compared to therapies that solely target VEGF-A.

2.2. AAV2 Vector Characteristics and Intravitreal Delivery

The sFLT01 transgene is delivered to retinal cells using an AAV serotype 2 vector.

  • Vector Choice (AAV2): AAV2 was selected as the delivery vehicle for the sFLT01 gene.[1] AAV2 is one of the most extensively characterized AAV serotypes for retinal gene therapy applications. It is known for its ability to transduce several types of retinal cells, particularly retinal ganglion cells and Müller cells, following intravitreal administration. It generally has a good safety profile in humans, though immune responses to the AAV2 capsid can occur and may limit efficacy.[1]
  • Intravitreal Delivery Route: The AAV2-sFLT01 vector was administered via a single injection into the vitreous cavity of the eye.[1] This route is less invasive than subretinal injection and is commonly performed in an outpatient setting. It allows the vector to diffuse through the vitreous humor, potentially providing access to a broader area of the retina. However, efficient transduction of outer retinal cells, such as the RPE (a major source of VEGF in nAMD), can be challenging for AAV2 when delivered intravitreally due to the barrier posed by the inner limiting membrane (ILM).[3]

2.3. Cellular Targets in the Retina for AAV2-Mediated Gene Delivery

Following intravitreal injection, AAV2 vectors primarily transduce cells located in the inner retina. The most commonly targeted cells include retinal ganglion cells (RGCs).[3] Müller glial cells, which span the entire thickness of the retina, can also be transduced, although typically with lower efficiency than RGCs with AAV2.[3] Once these cells are successfully transduced, they become local "biofactories," continuously synthesizing and secreting the sFLT01 protein. This secreted protein then diffuses into the vitreous humor and throughout the surrounding retinal tissues to exert its anti-VEGF effects.

The efficiency of AAV2 transduction via the intravitreal route can be quite variable. Factors influencing this include the physical barrier of the ILM, which can impede vector penetration to deeper retinal layers, and the presence of pre-existing neutralizing antibodies (NAbs) against the AAV2 capsid in the patient's vitreous or serum. These NAbs, resulting from prior natural exposure to wild-type AAV2, can bind to the vector particles and prevent them from transducing target cells, thereby limiting therapeutic efficacy.[1] The reliance on AAV2 delivered intravitreally presents a potential challenge: the primary cells transduced are inner retinal cells, while the main site of CNV pathology in nAMD often originates from the choroid and affects the RPE and outer retina. Although secreted sFLT01 can diffuse, achieving optimal therapeutic concentrations at the precise site of neovascularization in the outer retina might be difficult if the "biofactory" cells are relatively distant. This could necessitate higher overall vector doses, potentially increasing the risk of immunogenicity.

2.4. Expected Biological Effect: Inhibition of Angiogenesis and Vascular Permeability

The secreted sFLT01 protein, by binding and sequestering VEGF-A (and potentially PlGF), reduces the concentration of these free angiogenic factors available to interact with their cognate receptors (VEGFR-1, VEGFR-2, and Neuropilin-1) on the surface of vascular endothelial cells. This competitive inhibition is designed to downregulate critical endothelial cell functions such as proliferation, migration, and tube formation, which are essential steps in the process of neovascularization.[8] Consequently, the growth of abnormal new blood vessels should be suppressed.

Furthermore, by reducing VEGF activity, sFLT01 is expected to decrease abnormal vascular permeability. VEGF is a potent inducer of vascular leakage. Therefore, inhibiting its action should lead to a reduction in retinal edema and fluid accumulation within and beneath the retina, which are major contributors to the visual impairment seen in nAMD.[6] The sustained local production of sFLT01 is intended to maintain these anti-angiogenic and anti-permeability effects over a long period, offering a more stable control of the disease.

The inclusion of an IgG1 Fc domain in the sFLT01 construct is a common strategy in protein therapeutics, primarily aimed at enhancing protein stability and potentially facilitating expression and secretion.[1] While the Fc domain can sometimes be a source of immunogenicity, preclinical and Phase 1 clinical data for AAV2-sFLT01 did not report the formation of anti-sFLT01 antibodies, suggesting the protein itself was well-tolerated immunologically.[1] The entire therapeutic paradigm relies on achieving and maintaining adequate, sustained levels of sFLT01. Consequently, the variability in transgene expression observed in clinical trials, particularly if linked to factors like anti-AAV2 NAbs, poses a fundamental challenge to the consistent achievement of the intended biological effect and, therefore, to the overall viability of this therapeutic approach.

3. Developer History and Collaborations

3.1. Origination and Early Collaboration: Applied Genetic Technologies Corporation (AGTC) and Genzyme Corporation

The AAV2-sFLT01 gene therapy candidate was co-originated through a research collaboration between Applied Genetic Technologies Corporation (AGTC) and Genzyme Corporation.[15] This partnership, formally announced in December 2004, was established to combine AGTC's specialized expertise in AAV vector technology, including its novel high-yield AAV manufacturing capabilities, with Genzyme's extensive experience in gene therapy research and clinical development.[27] AGTC itself was founded on intellectual property originating from pioneering AAV gene therapy research conducted at the University of Florida, which also contributed to the early sFLT01 concepts with support from entities like the Juvenile Diabetes Research Foundation (JDRF) for related vascular research.[22] The initial scope of the AGTC-Genzyme collaboration was broad, encompassing the development of AAV vectors for a range of diseases beyond ophthalmology.[27] This collaboration model, where a smaller biotech with specialized platform technology partners with a larger pharmaceutical company possessing broader development and commercialization resources, is common in the industry.

3.2. Genzyme/Sanofi Leading Clinical Development and Manufacturing Evolution

Genzyme, which was subsequently acquired by Sanofi (initially operating as Sanofi Genzyme, then integrated into Sanofi), assumed the primary responsibility for the clinical development and eventual commercialization strategy for the AAV2-sFLT01 product candidate specifically for the treatment of wet AMD.[4] The pivotal Phase 1 clinical trial for nAMD (NCT01024998) was sponsored and funded by Sanofi Genzyme.[5]

A significant evolution in the collaboration occurred when Genzyme informed AGTC of its decision not to utilize AGTC's proprietary Herpes Simplex Virus (HSV)-based AAV manufacturing technology for the production of the AAV2-sFLT01 vector intended for the wet AMD program. The license agreement between the two companies was formally amended in December 2013 to reflect this change in manufacturing strategy. As a result of this decision, AGTC no longer anticipated deriving substantial revenue from this specific license arrangement with Genzyme for the wet AMD candidate.[28] This shift highlights how larger pharmaceutical partners may adapt or internalize technologies to align with their broader operational and strategic preferences, potentially altering the initial terms and expected outcomes for the originating biotech partner.

3.3. Status of JDRF Involvement

The Juvenile Diabetes Research Foundation (JDRF), now known as Breakthrough T1D, is listed as a "developer" of AAV2-sFLT01 in some pharmaceutical databases.[15] This association likely stems from JDRF's funding of early-stage, foundational academic research at the University of Florida. This research contributed to the scientific underpinnings of the sFLT01 concept or its potential application in diseases involving vascular pathology, which could include diabetic retinopathy—a complication of Type 1 diabetes, JDRF's primary focus.[22] However, direct and substantial funding by JDRF for the nAMD-specific clinical trial program (NCT01024998) is not evident from the available information. The connection illustrates how early research, supported by disease-specific organizations, can sometimes contribute to therapeutic concepts with broader applications.

3.4. Beacon Therapeutics and AAV2-sFLT01

Beacon Therapeutics is also listed as a "developer" of AAV2-sFLT01 in some industry databases.[14] Beacon Therapeutics was launched in June 2023 by Syncona, a healthcare investment company, following Syncona's acquisition of AGTC in November 2022.[31] Beacon Therapeutics' stated pipeline is focused on AGTC's former lead clinical asset, laru-zova (AGTC-501), for X-linked Retinitis Pigmentosa (XLRP), as well as a preclinical program for dry AMD (which is distinct from AAV2-sFLT01 for wet AMD) and another preclinical program for Cone-Rod Dystrophy licensed from the University of Oxford.[31]

Given that the development of AAV2-sFLT01 for nAMD had effectively stalled or been discontinued by Sanofi prior to AGTC's acquisition by Syncona (as detailed further in Section 7), it is highly unlikely that AAV2-sFLT01 is an active program within Beacon Therapeutics' current portfolio. The listing of Beacon Therapeutics as a developer in some databases may be an artifact of the general transfer of AGTC's broader intellectual property portfolio to Beacon, or it may reflect a historical association through AGTC's origination role, rather than indicating active development or prioritization of this specific candidate by Beacon. The absence of AAV2-sFLT01 from Beacon's public statements about its pipeline supports the conclusion that this asset was not carried forward as a lead candidate by the new entity.

4. Preclinical Development

4.1. Vector Design and Transgene Construct

The preclinical development of AAV2-sFLT01 utilized an AAV serotype 2 vector engineered to express the sFLT01 transgene. This transgene encodes a soluble fusion protein comprising domain 2 of the human Flt-1 receptor (VEGFR-1) and the Fc domain of human IgG1. Expression was driven by the chicken β-actin (CBA) promoter.[1] For preclinical studies, AAV2-sFLT01 vectors were produced using two different systems for comparison: a herpes simplex virus (HSV)-based production system and a more conventional triple-plasmid transfection method.[1]

4.2. In Vivo Efficacy Models and Administration Routes

AAV2-sFLT01 was evaluated in several established animal models of ocular neovascularization:

  • Rodent Models:
  • Murine Oxygen-Induced Retinopathy (OIR): This model mimics aspects of ischemic retinopathies. Intravitreal injection of AAV2-sFLT01 was shown to significantly reduce the area of retinal neovascularization compared to untreated or control vector-treated eyes (p<0.001).[7]
  • Murine Laser-Induced Choroidal Neovascularization (CNV): This model is commonly used to simulate key features of nAMD. Intravitreal administration of AAV2-sFLT01 effectively inhibited the development of CNV lesions.[7] Dose-response studies in this model indicated that intravitreal delivery required an approximately tenfold higher vector dose (minimum effective dose around 4×107 vector genomes (vg)/eye) to achieve a similar reduction in CNV area compared to subretinal delivery (minimum effective dose < 4×106 vg/eye). Following intravitreal delivery, sFLT01 expression was primarily observed in retinal ganglion cells, whereas subretinal delivery resulted in expression in photoreceptors and RPE cells.[22]
  • Non-Human Primate (NHP) Models (Cynomolgus Monkeys):
  • Laser-Induced CNV: In a primate model of laser-induced CNV, intravitreal injection of AAV2-sFLT01 demonstrated efficacy in inhibiting CNV, with effects observed at 5 months post-vector administration.[7]
  • Long-Term Safety and Expression Study: A comprehensive 12-month toxicology and biodistribution study was conducted in cynomolgus monkeys. Animals received a single intravitreal injection of AAV2-sFLT01 at doses of 2.4×109 vg/eye (low dose) or 2.4×1010 vg/eye (high dose), or vehicle control. Some animals were followed for an additional 6 months (total 18 months).[1]

4.3. Key Preclinical Efficacy Findings

  • Sustained sFLT01 Expression: A critical finding from the NHP studies was the demonstration of long-term, dose-dependent sFLT01 protein expression in the eye following a single intravitreal injection. In the aqueous humor of NHPs, sFLT01 protein levels typically peaked around 1-month post-administration and remained relatively constant for at least 12 months, with one animal in the high-dose group showing sustained expression for up to 18 months.[1] Detectable levels of sFLT01 were also found in the vitreous humor at the study's termination.[1] This sustained expression was a key proof-of-concept for the gene therapy approach.
  • VEGF Neutralization and Anti-Angiogenic Effects: The expressed sFLT01 protein effectively inhibited neovascularization in both the murine OIR and laser-induced CNV models, as well as in the primate laser-induced CNV model.[7] The mechanism involves the high-affinity binding of sFLT01 to VEGF (and potentially PlGF), thereby preventing these factors from stimulating endothelial cell proliferation and new vessel formation.[8]

4.4. Preclinical Safety and Tolerability Profile

  • Ocular Inflammation: The most notable safety finding in the NHP studies was the occurrence of mild to moderate, generally self-resolving, vitreal inflammation (characterized by "haze and cells" on ophthalmoscopy). This inflammation was observed predominantly in the high-dose (2.4×1010 vg) group.[1] The onset was typically within 1-3 months post-injection, and in most animals, it resolved by 5 months, although very low levels could persist longer.[1] Histopathological examination of eyes from high-dose NHPs revealed minimal to moderate inflammatory cell infiltrates (lymphocytes, macrophages, plasma cells) in the trabecular meshwork, anterior uvea, and vitreous, and occasionally perivascularly in the retina. Importantly, these inflammatory changes were not associated with structural damage to the retina or other critical ocular structures.[1] This capsid-mediated inflammation was a significant preclinical observation, foreshadowing potential immunogenicity challenges in human trials.
  • Immunogenicity:
  • The ocular inflammation observed in NHPs was primarily attributed to an immune response against the AAV2 capsid, rather than the sFLT01 transgene product. This conclusion was supported by studies showing that AAV2 vectors lacking a transgene (AAV2-null) also induced a similar inflammatory response.[1]
  • Crucially, no antibodies against the sFLT01 protein itself were detected in the serum or aqueous humor of NHPs at any time point during the 12-month study.[1]
  • A dose- and time-dependent increase in anti-AAV2 capsid antibody titers was observed in both serum and aqueous humor of the treated NHPs.[1]
  • The presence of pre-existing anti-AAV2 antibody titers in one NHP was correlated with lower sFLT01 expression levels, suggesting that pre-existing immunity to AAV2 could significantly impair vector transduction efficiency and subsequent transgene expression.[1] This was a critical early signal of a potential hurdle for clinical translation.
  • Minimal T-cell responses against the AAV2 capsid were detected in a few NHPs, but these did not correlate with the severity of inflammation or antibody titers. No T-cell response to the sFLT01 protein was detected.[1]
  • Systemic Safety and Biodistribution: AAV2-sFLT01 was found to be systemically well-tolerated in both rodent and NHP studies.[1] Biodistribution analyses were critical for assessing systemic exposure. These studies demonstrated that the AAV2 vector DNA was predominantly localized to the injected eye.[1] Only trace amounts of vector DNA were detected transiently or at very low levels in some non-ocular tissues (such as the optic nerve of the injected eye, very rarely in the contralateral optic nerve, and sporadically in systemic organs like the spleen and liver in rats). Importantly, there was no evidence of sFLT01 transgene expression in these remote tissues.[1] Consistent with localized expression, sFLT01 protein was not consistently detected in the serum of NHPs.[1] These biodistribution findings were crucial for the overall safety assessment, alleviating concerns about widespread vector dissemination or off-target systemic effects from either the vector or long-term VEGF suppression.
  • Retinal Function and Structure: Long-term (12-month) VEGF suppression mediated by AAV2-sFLT01 in NHPs did not lead to any histological evidence of retinal degeneration or adverse changes in retinal function as assessed by electroretinograms (ERGs).[1] Fluorescein angiograms and intraocular pressure measurements also remained generally normal and comparable between treated and control groups, aside from transient haze related to inflammation in some high-dose animals.[1]
  • Impact of Vector Production Method: Comparative studies in NHPs using AAV2-sFLT01 produced by either an HSV-based system or a triple-transfection method showed that both vector preparations induced varying degrees of inflammation. This further supported the conclusion that the AAV2 capsid itself was the primary inflammatory stimulus, rather than impurities specific to one production method.[1]

The preclinical data, particularly the sustained expression and efficacy in NHP CNV models [7], provided a strong rationale for advancing AAV2-sFLT01 into clinical trials for nAMD, supporting the "one-time treatment" paradigm. However, the murine studies highlighting the dose differential between intravitreal and subretinal delivery for comparable efficacy [22] also underscored the complexities of choosing the optimal delivery route and the inherent trade-offs between invasiveness and transduction efficiency for different retinal targets.

5. Clinical Development for Neovascular Age-Related Macular Degeneration (nAMD)

The clinical development of AAV2-sFLT01 for nAMD centered on a Phase 1 trial designed to assess its safety, tolerability, and preliminary biological activity.

5.1. Phase 1 Clinical Trial (NCT01024998)

  • Trial Title and Identification: The study was titled "A Phase 1, Open-Label, Multi-Center, Dose-Escalating, Safety and Tolerability Study of a Single Intravitreal Injection of AAV2-sFLT01 in Patients With Neovascular Age-Related Macular Degeneration" and is registered on ClinicalTrials.gov as NCT01024998.[2]
  • Sponsor: The trial was sponsored by Genzyme, a Sanofi Company.[5]
  • Study Design: This was an open-label, dose-escalating, multicenter study conducted at four outpatient retina clinics in the United States. Patients were enrolled sequentially into cohorts.[2]
  • Patient Population: A total of 19 patients with advanced nAMD were enrolled between May 2010 and July 2014. Eligible patients were aged 50 years or older and had a baseline Best Corrected Visual Acuity (BCVA) of 20/100 or worse in the study eye. Patients in the initial four dose-escalation cohorts (Cohorts 1-4) typically had evidence of subfoveal disciform scarring, representing advanced disease. A fifth cohort (Cohort 5, maximum tolerated dose extension) enrolled patients who had previously shown responsiveness to standard anti-VEGF therapy within 12 months prior to enrollment, suggesting some potential for anatomical or functional improvement.[2]
  • Dosing Cohorts: Patients received a single intravitreal injection of AAV2-sFLT01 in one eye at one of the following dose levels:
  • Cohort 1: 2×108 vector genomes (vg) (n=3)
  • Cohort 2: 2×109 vg (n=3)
  • Cohort 3: 6×109 vg (n=3)
  • Cohort 4: 2×1010 vg (n=3)
  • Cohort 5 (Maximum Tolerated Dose extension): 2×1010 vg (n=7).[2]
  • Study Duration: All patients were monitored for a 52-week core study period. Participants were also encouraged to enroll in an extended follow-up program for up to 4 years to assess long-term safety and expression.[2]
  • Primary Endpoint: The primary objective was to assess the safety and tolerability of a single intravitreal injection of AAV2-sFLT01, primarily through the monitoring and reporting of eye-related adverse events.[2]
  • Secondary/Exploratory Endpoints: These included assessments of biological activity, such as changes from baseline in subretinal and/or intraretinal fluid measured by optical coherence tomography (OCT), changes in BCVA, and levels of sFLT01 protein detected in the aqueous humor. The need for rescue anti-VEGF injections was also an important exploratory outcome, although not always prominently reported as a primary success metric in initial publications.[2]

5.2. Key Safety Findings (NCT01024998)

The Phase 1 trial results indicated that AAV2-sFLT01 was generally safe and well-tolerated across all dose levels tested, and no dose-limiting toxicities were observed.[2]

  • Intraocular Inflammation: The most significant drug-related adverse event was intraocular inflammation (uveitis or vitritis). Two patients in Cohort 4 (who received the 2×1010 vg dose) experienced such inflammation, which was deemed possibly related to the study drug. This inflammation was managed successfully and resolved with topical corticosteroid treatment.[5] This clinical finding was consistent with the AAV2 capsid-mediated inflammation observed in the preclinical NHP studies.
  • Other Adverse Events: One patient experienced pyrexia (fever) that was also considered possibly related to the study drug.[5] One patient in Cohort 5 experienced a significant decrease in vision between weeks 26 and 52; however, this was not thought to be related to the AAV2-sFLT01 vector.[5]

5.3. Key Efficacy Findings (NCT01024998)

The efficacy results from the Phase 1 trial were mixed, showing some signals of biological activity but also highlighting significant variability.

  • sFLT01 Protein Expression: Detectable levels of sFLT01 protein in the aqueous humor were identified in 5 out of the 10 patients who received the highest dose of 2×1010 vg (combining Cohorts 4 and 5).[2] In these patients who demonstrated expression, sFLT01 levels peaked at a mean of 73.7 ng/mL (range 32.7–112.0 ng/mL) by week 26, with a slight decrease to a mean of 53.2 ng/mL by week 52.[5] This demonstrated that the gene therapy could lead to intraocular protein production, but expression was not universal among high-dose recipients. The variability in expression was a significant finding.[6]
  • Impact of Baseline Anti-AAV2 Antibodies: A critical observation was the apparent correlation between baseline anti-AAV2 neutralizing antibody (NAb) status and subsequent sFLT01 expression. Four of the five patients who expressed sFLT01 at the highest dose were negative for anti-AAV2 serum antibodies at baseline, while the fifth had a very low NAb titer (1:100). Conversely, four of the five patients who did not express sFLT01 at this dose had higher baseline anti-AAV2 NAb titers (1:400 or greater).[5] This strongly suggested that pre-existing immunity to the AAV2 vector could abrogate transgene expression and, therefore, therapeutic efficacy. This remains a pivotal challenge for AAV-based gene therapies.
  • Anatomical Outcomes (Retinal Fluid): Of the 19 patients enrolled, 11 had intraretinal or subretinal fluid at baseline that was considered potentially reversible. Among these 11 patients, six (55%) demonstrated a substantial reduction in fluid as measured by OCT. For four of these six patients, the reduction in fluid was sustained over the study period.[2] However, five of these 11 patients showed no reduction in fluid.[5]
  • Visual Acuity (BCVA): Changes in BCVA following treatment did not consistently correlate with other parameters of biological activity, such as sFLT01 expression levels or the degree of fluid reduction.[2] While some individual patients who experienced fluid reduction also showed vision improvement, this was not a uniform finding.[5]
  • Anti-VEGF Rescue Injections: The primary publications and summaries of NCT01024998 focus heavily on safety and sFLT01 expression levels, with anatomical changes noted in a subset of patients.[5] Some overviews describe the anatomo-functional results as "not significant".[12] Unlike some later-stage gene therapy trials for nAMD that prominently feature a reduction in the need for rescue anti-VEGF injections as a key efficacy endpoint [11], this was not highlighted as a major success for AAV2-sFLT01 in the available reports. This suggests that a clinically compelling reduction in treatment burden was likely not uniformly achieved or robustly demonstrated in this early-phase study.

5.4. Interpretation of Phase 1 Results

The investigators concluded that a single intravitreal injection of AAV2-sFLT01 appeared to be safe and was generally well-tolerated at all doses tested in patients with advanced nAMD.[2] Evidence of biological activity, including measurable sFLT01 protein expression in the eye and anatomical improvements (fluid reduction) on OCT, was observed in a subset of patients, particularly those receiving the highest vector dose.[2]

However, significant variability in transgene expression was a key challenge, with pre-existing neutralizing antibodies to the AAV2 capsid appearing to be a major contributing factor to the lack of expression in some patients.[5] The overall clinical efficacy signal, in terms of consistent and robust improvements in visual acuity or a clear reduction in the need for rescue anti-VEGF therapy across the treated population, was modest.[2] The study authors suggested that additional research would be necessary to identify and address the sources of variability in expression and anti-permeability activity to optimize the therapy.[5]

The modest and variable clinical efficacy, despite some patients achieving potentially therapeutic sFLT01 levels, raised questions about whether higher or more consistent expression levels were needed, or if sFLT01's anti-VEGF activity alone was sufficient to robustly control nAMD in all patients, especially those with advanced disease. The decision not to proceed to later-phase trials for nAMD after this Phase 1 study likely stemmed from a combination of these factors: the AAV2 NAb issue, the observed expression variability, the modest efficacy signals, and the highly competitive landscape of nAMD treatments, where existing protein drugs, though burdensome, are highly effective.

Table 1: Summary of Phase 1 Clinical Trial (NCT01024998) for AAV2-sFLT01 in nAMD

ParameterDetails
Trial IdentifierNCT01024998 5
SponsorGenzyme, a Sanofi Company 5
PhasePhase 1 2
Primary IndicationNeovascular (wet) Age-Related Macular Degeneration (advanced) 2
Study DesignOpen-label, dose-escalating, multicenter (USA) 2
Number of Patients19 2
Dosage Cohorts (vg/eye)2×108, 2×109, 6×109, 2×1010 (including MTD extension cohort at 2×1010 vg) 2
Primary EndpointSafety and tolerability (eye-related adverse events) 2
Key Safety FindingsGenerally safe and well-tolerated. No dose-limiting toxicities. Possible drug-related AEs: intraocular inflammation (2 patients, high dose, resolved with steroids), pyrexia (1 patient). 5
Key Efficacy Findings- sFLT01 Expression: Detected in aqueous humor of 5/10 patients at highest dose; levels peaked at week 26 (mean 73.7 ng/mL), sustained to week 52 (mean 53.2 ng/mL). 5<br>- Impact of NAbs: Expression correlated negatively with baseline anti-AAV2 NAb titers. 5<br>- Anatomical Changes (OCT): 6/11 eligible patients showed substantial fluid reduction (sustained in 4). 2<br>- Visual Acuity (BCVA): Inconsistent changes, did not correlate well with expression or fluid reduction. 2<br>- Anti-VEGF Rescue: Not reported as a significant positive outcome; overall anatomo-functional results deemed "not significant" in some summaries. 12
Overall ConclusionSingle intravitreal injection of AAV2-sFLT01 seemed safe and well tolerated. Biological activity observed in a subset. Variability in expression (linked to NAbs) was a challenge. Further studies needed to address variability. 5

6. Development for Other Indications (e.g., Diabetic Retinopathy)

6.1. Status of Development for Diabetic Retinopathy

In addition to nAMD, AAV2-sFLT01 was also explored or considered as a potential therapeutic for diabetic retinopathy, another significant ocular condition characterized by VEGF-driven neovascularization and vascular permeability.[15] However, according to available development databases, the program for diabetic retinopathy was officially discontinued.[15] The specific phase of development that AAV2-sFLT01 reached for diabetic retinopathy before its discontinuation is not clearly detailed in the provided information, but it did not progress to late-stage clinical trials.

6.2. Rationale for Discontinuation (if available)

The specific reasons for the discontinuation of AAV2-sFLT01 development for diabetic retinopathy are not explicitly stated in the provided research materials.[9] It is reasonable to infer that the challenges encountered in the nAMD program—namely, the variability in transgene expression, the impact of pre-existing neutralizing antibodies to the AAV2 vector, the modest overall efficacy signals, and concerns about capsid-mediated immunogenicity—likely played a role in the decision. Pharmaceutical companies often make strategic portfolio decisions based on the overall risk-benefit profile, the competitive landscape, and the likelihood of successful development. The lack of robust, consistent positive data from the nAMD program may have diminished confidence in pursuing the same vector-transgene combination for diabetic retinopathy, which presents its own set of complexities. The discontinuation for diabetic retinopathy, alongside the halted development for nAMD, suggests that the AAV2-sFLT01 platform likely faced fundamental challenges related to vector performance or transgene expression consistency that were not necessarily indication-specific. The absence of detailed public announcements regarding the reasons for early-stage discontinuation is common in the pharmaceutical industry when programs do not meet predefined progression criteria.

7. Current Development Status and Future Outlook

7.1. Summary of Current Status

As of the latest available information, the development of AAV2-sFLT01 (also known as GZ-402663) has largely ceased for its primary intended indications:

  • Neovascular AMD: Following the completion of the Phase 1 clinical trial (NCT01024998) by Genzyme/Sanofi, there have been no recent reports of further clinical development for this indication since approximately 2018-2020.[5] The program is considered stalled or discontinued for nAMD.
  • Diabetic Retinopathy: Development for this indication was officially discontinued.[15]
  • Overall: AAV2-sFLT01 is not being actively pursued by Sanofi. Furthermore, Beacon Therapeutics, which emerged from the acquisition of AGTC (an originator of the therapy), does not feature AAV2-sFLT01 in its current publicly disclosed pipeline, which is focused on other ophthalmology gene therapy assets.[15]

7.2. Factors Influencing Development Progression and Discontinuation

Several key factors likely contributed to the decision to halt further development of AAV2-sFLT01:

  • Variable Transgene Expression: The Phase 1 nAMD trial demonstrated inconsistent levels of sFLT01 protein expression among patients, even at the highest doses. This variability makes it difficult to predict patient response and achieve consistent therapeutic effects.[2]
  • Immunogenicity:
  • Pre-existing Neutralizing Antibodies (NAbs) to AAV2: A significant finding was the negative impact of baseline anti-AAV2 NAbs on sFLT01 expression. Since a considerable portion of the general population has pre-existing immunity to AAV2 due to natural exposure, this posed a major hurdle for broad clinical application.[5]
  • AAV2 Capsid-Induced Inflammation: Although the intraocular inflammation observed was generally mild to moderate and manageable with topical steroids, the potential for AAV2 capsid-induced immune responses remained a concern, particularly with the higher vector doses required for adequate expression via intravitreal delivery.[1]
  • Clinical Efficacy Signal: While some patients in the Phase 1 trial showed biological activity (e.g., fluid reduction), the overall anatomo-functional results were not consistently robust or compelling enough to clearly demonstrate a significant advantage over existing, highly effective anti-VEGF protein therapies, especially when weighed against the aforementioned challenges.[2] The high bar set by current nAMD treatments makes it difficult for new therapies, particularly those with novel mechanisms and potential risks, to show a clear benefit.
  • Manufacturing and Development Strategy Shifts: Genzyme/Sanofi's decision not to use AGTC's HSV-based manufacturing technology for the AAV vector indicated internal shifts in the development and production strategy.[28] While not a direct cause for discontinuation, such changes can impact timelines and program continuity.
  • Strategic Portfolio Decisions: Pharmaceutical companies like Sanofi conduct periodic reviews of their R&D pipelines. Programs that do not meet certain efficacy thresholds, face significant development hurdles, or do not align with evolving strategic priorities may be discontinued to reallocate resources to more promising candidates.[43] The combination of technical challenges and a competitive therapeutic landscape likely influenced such a decision for AAV2-sFLT01.

7.3. Challenges in Ocular Gene Therapy Highlighted by AAV2-sFLT01

The AAV2-sFLT01 program illuminated several critical challenges inherent in the development of ocular gene therapies, particularly those using AAV vectors:

  • Vector Immunogenicity: The issue of pre-existing NAbs limiting transduction and de novo immune responses to the viral capsid remain significant obstacles that can affect safety and efficacy.[1]
  • Consistent and Predictable Transgene Expression: Achieving therapeutically relevant and predictable levels of transgene expression in all targeted patients is crucial but difficult to attain with current technologies, especially with intravitreal delivery.[5]
  • Optimizing Vector Delivery: The choice of vector serotype and delivery route (e.g., intravitreal versus subretinal) significantly impacts which retinal cells are transduced and the efficiency of transduction. For diseases like nAMD, where pathology is often in the outer retina, intravitreal delivery of AAV2 faces limitations.[3]
  • Translating Preclinical Success to Human Efficacy: While animal models provide essential proof-of-concept, the complexity and heterogeneity of human diseases like nAMD mean that preclinical success does not always translate directly to robust clinical efficacy.[13]
  • The Competitive Therapeutic Landscape: For indications like nAMD where effective (albeit burdensome) treatments exist, new gene therapies must demonstrate a very clear and substantial advantage in terms of efficacy, durability, or safety to gain acceptance and justify further development.

7.4. Potential Future Directions or Lessons Learned

Despite the discontinuation of AAV2-sFLT01, the program provided valuable lessons that have informed and continue to shape the field of ocular gene therapy:

  • Improved Vector Engineering: The challenges with AAV2 have spurred research into novel AAV capsids (e.g., engineered variants, alternative serotypes) with improved retinal transduction profiles, reduced immunogenicity, and the ability to evade pre-existing NAbs.
  • Patient Stratification: The experience highlighted the importance of screening patients for NAb status and potentially other biomarkers to identify those most likely to respond to AAV-mediated gene therapy.
  • The "Biofactory" Concept Remains Viable: The underlying principle of using gene therapy to create an intraocular biofactory for sustained production of therapeutic proteins like anti-VEGF agents remains highly attractive. Newer gene therapy candidates for nAMD are actively being developed, leveraging insights from earlier programs like AAV2-sFLT01.[10] These often incorporate different AAV serotypes, modified transgenes, or alternative delivery strategies.
  • Potential of the sFLT01 Molecule: The challenges faced by AAV2-sFLT01 appear to be more related to the gene delivery and expression system rather than a fundamental flaw in the sFLT01 protein's anti-angiogenic capacity. Modified versions of sFLT01 [8] or alternative delivery platforms could potentially harness its therapeutic benefits more effectively in the future.

The journey of AAV2-sFLT01 underscores the iterative nature of scientific and medical progress. While this specific candidate did not proceed to late-stage development, the knowledge gained regarding vector immunogenicity, transgene expression variability, and the complexities of treating nAMD with gene therapy has been invaluable for the ongoing efforts to develop more effective and durable treatments for blinding retinal diseases.

8. Conclusion

AAV2-sFLT01 (GZ-402663) represented an important early endeavor in the application of gene therapy to address neovascular age-related macular degeneration and other ocular diseases characterized by pathological angiogenesis. Developed through an initial collaboration between Applied Genetic Technologies Corporation (AGTC) and Genzyme (later Sanofi), the therapeutic concept centered on using an AAV2 vector to deliver the sFLT01 gene, enabling sustained intraocular production of a soluble VEGF-neutralizing protein. The primary goal was to reduce the significant treatment burden associated with frequent anti-VEGF protein injections.

Preclinical studies in rodent and non-human primate models demonstrated promising results, including long-term expression of sFLT01 and efficacy in inhibiting neovascularization. However, these studies also highlighted potential challenges, notably a dose-dependent AAV2 capsid-mediated intraocular inflammation and the impact of pre-existing neutralizing antibodies against AAV2 on transgene expression levels.

The subsequent Phase 1 clinical trial (NCT01024998) in patients with advanced nAMD confirmed that AAV2-sFLT01 was generally safe and well-tolerated. Some patients, particularly at the highest dose, exhibited measurable sFLT01 expression and anatomical improvements. However, the trial also underscored the critical hurdles identified preclinically: transgene expression was variable and appeared to be significantly hampered by baseline anti-AAV2 neutralizing antibodies in a subset of patients. The overall clinical efficacy, in terms of consistent visual improvement or a clear reduction in the need for rescue anti-VEGF treatments, was not sufficiently robust to support further development in the competitive nAMD landscape.

Consequently, the development of AAV2-sFLT01 for nAMD did not progress beyond Phase 1, and its exploration for diabetic retinopathy was also discontinued. The program's trajectory illustrates common challenges in drug development, where initial safety and some biological activity do not always translate into a compelling efficacy and risk-benefit profile needed for late-stage development and regulatory approval, especially when effective alternative treatments exist.

Despite its discontinuation, the AAV2-sFLT01 program has contributed valuable knowledge to the field of ocular gene therapy. It provided important insights into AAV2 vector behavior in the human eye, the significant impact of host immune responses on vector efficacy, and the complexities of achieving consistent, long-term therapeutic transgene expression. These lessons have informed the design and development of subsequent generations of gene therapies for retinal diseases, which continue to explore novel vectors, delivery strategies, and transgene constructs to overcome the limitations encountered by early candidates like AAV2-sFLT01. The pursuit of a durable, single-treatment solution for chronic retinal conditions like nAMD remains a critical goal in ophthalmology.

Works cited

  1. Preclinical Safety Evaluation of AAV2-sFLT01—A Gene Therapy for ..., accessed May 29, 2025, https://pmc.ncbi.nlm.nih.gov/articles/PMC3034852/
  2. 249. Preliminary Results of a Phase 1, Open-Label, Safety and Tolerability Study of a Single Intravitreal Injection of AAV2-sFLT01 in Patients with Neovascular Age-Related Macular Degeneration - ResearchGate, accessed May 29, 2025, https://www.researchgate.net/publication/312436340_249_Preliminary_Results_of_a_Phase_1_Open-Label_Safety_and_Tolerability_Study_of_a_Single_Intravitreal_Injection_of_AAV2-sFLT01_in_Patients_with_Neovascular_Age-Related_Macular_Degeneration
  3. Gene therapy of the human retina - Wikipedia, accessed May 29, 2025, https://en.wikipedia.org/wiki/Gene_therapy_of_the_human_retina
  4. Preclinical Safety Evaluation of AAV2-sFLT01— A Gene Therapy for Age-related Macular Degeneration - ResearchGate, accessed May 29, 2025, https://www.researchgate.net/publication/49647029_Preclinical_Safety_Evaluation_of_AAV2-sFLT01-_A_Gene_Therapy_for_Age-related_Macular_Degeneration
  5. Intravitreous injection of AAV2-sFLT01 in patients with advanced neovascular age-related macular degeneration: a phase 1, open-label trial - PubMed, accessed May 29, 2025, https://pubmed.ncbi.nlm.nih.gov/28526489/
  6. Intravitreous injection of AAV2-sFLT01 in patients with advanced neovascular age-related macular degeneration: A phase 1, open-label trial - ResearchGate, accessed May 29, 2025, https://www.researchgate.net/publication/317025385_Intravitreous_injection_of_AAV2-sFLT01_in_patients_with_advanced_neovascular_age-related_macular_degeneration_A_phase_1_open-label_trial
  7. An Anti-VEGF Gene Therapy for Neovascular Age-related Macular Degeneration - Efficacy and Safety Studies in Murine and Primate Models | IOVS, accessed May 29, 2025, https://iovs.arvojournals.org/article.aspx?articleid=2366678
  8. Intravitreal administration of AAV2-sFLT01 (~2 × 109 vg) to C57BL/6... - ResearchGate, accessed May 29, 2025, https://www.researchgate.net/figure/ntravitreal-administration-of-AAV2-sFLT01-2-109-vg-to-C57BL-6-mouse-eyes-resulted-in_fig5_47556306
  9. Gene Therapy for Retinal Disease - Review of Ophthalmology, accessed May 29, 2025, https://www.reviewofophthalmology.com/article/gene-therapy-for-retinal-disease
  10. Targeting vascular endothelial growth factor using retinal gene therapy - Chung, accessed May 29, 2025, https://atm.amegroups.org/article/view/54173/html
  11. Safety and Efficacy of Ixoberogene Soroparvovec in Neovascular Age-Related Macular Degeneration in the United States (OPTIC): A, accessed May 29, 2025, https://jdc.jefferson.edu/cgi/viewcontent.cgi?article=1208&context=willsfp
  12. Recent Developments in Gene Therapy for Neovascular Age-Related Macular Degeneration: A Review - PubMed Central, accessed May 29, 2025, https://pmc.ncbi.nlm.nih.gov/articles/PMC10740940/
  13. Gene therapy in AMD: Promises and challenges - Retina Specialist, accessed May 29, 2025, https://www.retina-specialist.com/article/gene-therapy-in-amd-promises-and-challenges
  14. AAV2sFLT01(Genzyme Corp.) - Drug Targets, Indications, Patents - Patsnap Synapse, accessed May 29, 2025, https://synapse.patsnap.com/drug/291d7c54238348da851b0bc81a53582e
  15. AAV2sFLT 01 - Beacon Therapeutics - AdisInsight - Springer, accessed May 29, 2025, https://adisinsight.springer.com/drugs/800024449
  16. Gene Therapy for Inherited and Rare Retinal Disease | Retinal ..., accessed May 29, 2025, https://retinalphysician.com/issues/2020/special-edition/gene-therapy-for-inherited-and-rare-retinal-disease/
  17. AAV2-SFLT01 Drug Profile - Ozmosi, accessed May 29, 2025, https://pryzm.ozmosi.com/product/14945
  18. Surgical gene therapy study for wet AMD yields mixed results - Ophthalmology Times, accessed May 29, 2025, https://www.ophthalmologytimes.com/view/surgical-gene-therapy-study-wet-amd-yields-mixed-results
  19. GZ402663 News - LARVOL Sigma, accessed May 29, 2025, https://sigma.larvol.com/product.php?e1=680&tab=newstrac
  20. Inhibition of pathological brain angiogenesis through systemic delivery of AAV vector expressing soluble FLT1 - PMC - PubMed Central, accessed May 29, 2025, https://pmc.ncbi.nlm.nih.gov/articles/PMC4636448/
  21. Preclinical safety evaluation of AAV2-sFLT01- a gene therapy for age-related macular degeneration - PubMed, accessed May 29, 2025, https://pubmed.ncbi.nlm.nih.gov/21119620/
  22. Minimal Effective Dosing of a Novel Recombinant Form of VEGF Soluble Receptor 1 (sFlt-1) Delivered via AAV Vector in Inhibiting Choroidal Neovascularization in a Murine Model | IOVS, accessed May 29, 2025, https://iovs.arvojournals.org/article.aspx?articleid=2376829
  23. Low risk to retina from sustained suppression of VEGF - JCI, accessed May 29, 2025, https://www.jci.org/articles/view/129861
  24. Gene Therapy Intervention in Neovascular Eye Disease: A Recent Update - PMC, accessed May 29, 2025, https://pmc.ncbi.nlm.nih.gov/articles/PMC7544979/
  25. A Penetrable AAV2 Capsid Variant for Efficient Intravitreal Gene Delivery to the Retina - PMC - PubMed Central, accessed May 29, 2025, https://pmc.ncbi.nlm.nih.gov/articles/PMC11702840/
  26. Intravitreal delivery of a novel AAV vector targets ON bipolar cells and restores visual function in a mouse model of complete congenital stationary night blindness - PubMed Central, accessed May 29, 2025, https://pmc.ncbi.nlm.nih.gov/articles/PMC4612567/
  27. Gene Therapy Collaboration - HUM-MOLGEN news, accessed May 29, 2025, https://hum-molgen.org/NewsGen/12-2004/000020.html
  28. S-1 - SEC.gov, accessed May 29, 2025, https://www.sec.gov/Archives/edgar/data/1273636/000119312514008046/d615962ds1.htm
  29. Statement from Aaron J. Kowalski, PhD, CEO of Breakthrough T1D, Formerly JDRF, the Leading Global Type 1 Diabetes Research and Advocacy Organization, on NIH Indirect Costs Cuts, accessed May 29, 2025, https://www.breakthrought1d.org/for-the-media/press-releases/statement-from-aaron-j-kowalski-phd-ceo-of-breakthrough-t1d-formerly-jdrf-the-leading-global-type-1-diabetes-research-and-advocacy-organization-on-nih-indirect-costs-cuts/
  30. Breakthrough T1D: Type 1 Diabetes, accessed May 29, 2025, https://www.jdrf.org/
  31. Beacon Therapeutics Launch, accessed May 29, 2025, https://www.beacontx.com/news-and-events/beacon-therapeutics-launch/
  32. Beacon Therapeutics launches with £96 million ($120 million) to develop a new generation of gene therapies for retinal diseases resulting in blindness - GlobeNewswire, accessed May 29, 2025, https://www.globenewswire.com/news-release/2023/06/12/2685957/0/en/Beacon-Therapeutics-launches-with-96-million-120-million-to-develop-a-new-generation-of-gene-therapies-for-retinal-diseases-resulting-in-blindness.html
  33. AAV Gene Therapy - Beacon Therapeutics, accessed May 29, 2025, https://www.beacontx.com/aav-gene-therapy/
  34. Beacon's rare eye disease gene therapy signals vision function ..., accessed May 29, 2025, https://www.fiercebiotech.com/biotech/beacons-rare-eye-disease-gene-therapy-signals-vision-function-improvements-early-phase-2
  35. Beacon Therapeutics Announces Positive Phase 2 Interim 6-Month Data from DAWN Trial of Laru-zova in Patients with X-linked Retinitis Pigmentosa (XLRP) at ARVO 2025 - GlobeNewswire, accessed May 29, 2025, https://www.globenewswire.com/news-release/2025/05/06/3075349/30580/en/Beacon-Therapeutics-Announces-Positive-Phase-2-Interim-6-Month-Data-from-DAWN-Trial-of-Laru-zova-in-Patients-with-X-linked-Retinitis-Pigmentosa-XLRP-at-ARVO-2025.html
  36. Beacon Therapeutics Announces Positive 3-Month Data from Phase 2 DAWN Trial of laru-zova (AGTC-501) in Patients with X-Linked Retinitis Pigmentosa (XLRP) - PR Newswire, accessed May 29, 2025, https://www.prnewswire.com/news-releases/beacon-therapeutics-announces-positive-3-month-data-from-phase-2-dawn-trial-of-laru-zova-agtc-501-in-patients-with-x-linked-retinitis-pigmentosa-xlrp-302324627.html
  37. Beacon Therapeutics: Home, accessed May 29, 2025, https://www.beacontx.com/
  38. Pipeline - Beacon Therapeutics, accessed May 29, 2025, https://www.beacontx.com/pipeline/
  39. Sanofi - SEC.gov, accessed May 29, 2025, https://www.sec.gov/Archives/edgar/data/1121404/000104746914001951/a2217900z20-f.htm
  40. Clinical Study Results Medicines, including Rare Diseases - Sanofi, accessed May 29, 2025, https://www.sanofi.com/en/our-science/clinical-trials-and-results/clinical-study-results/medicines
  41. From Trials to Treatment: Real-World Applications in Medical and Surgical Retina Part 3 of 3, accessed May 29, 2025, https://evolvemeded.com/specialty/retina/from-trials-to-treatment-real-world-applications-in-medical-and-surgical-retina-part-3-of-3/27234/
  42. Our Product Pipeline | Sanofi, accessed May 29, 2025, https://www.sanofi.com/en/our-science/our-pipeline
  43. Sanofi delivers 2018 business EPS growth of 5.1% at CER - Feb 7, 2019, accessed May 29, 2025, https://www.news.sanofi.us/2019-02-07-Sanofi-delivers-2018-business-EPS-growth-of-5-1-at-CER
  44. FORM 20-F 2012 - Annual Reports, accessed May 29, 2025, https://www.annualreports.com/HostedData/AnnualReportArchive/s/NYSE_SNY_2012.pdf
  45. accessed January 1, 1970, https://www.evaluate.com/vantage/articles/events/conferences/aao-2019-gene-therapy-updates-keep-coming
  46. accessed January 1, 1970, https://eyewire.news/news/tag/aav2-sflt01
  47. Rethinking the potential and necessity of drug delivery systems in neovascular age-related macular degeneration therapy - PubMed Central, accessed May 29, 2025, https://pmc.ncbi.nlm.nih.gov/articles/PMC10242387/

Published at: May 29, 2025

This report is continuously updated as new research emerges.

MedPath

Empowering clinical research with data-driven insights and AI-powered tools.

© 2025 MedPath, Inc. All rights reserved.