A Comprehensive Monograph on Anecortave: A Novel Angiostatic Cortisene from Clinical Promise to Discontinuation

Executive Summary

This report provides a comprehensive scientific and clinical monograph on Anecortave (DrugBank ID: DB12081), an investigational small molecule. Anecortave is the principal active metabolite of the prodrug Anecortave Acetate, which was developed by Alcon, Inc. under the proposed trade name Retaane. Anecortave Acetate was engineered as a first-in-class "angiostatic cortisene," a synthetic steroid derivative designed to potently inhibit angiogenesis—the formation of new blood vessels—while being devoid of the glucocorticoid activity and associated side effects typical of corticosteroids.

The primary therapeutic target for Anecortave Acetate was exudative (wet) age-related macular degeneration (AMD), a leading cause of severe vision loss. Its development was characterized by significant innovation, most notably a multi-faceted, downstream mechanism of action that targeted multiple steps in the angiogenic cascade, and a novel drug delivery system. This system, known as the posterior juxtascleral depot (PJD), utilized a specialized cannula to place a slow-release suspension of the drug behind the eye, offering the potential for sustained therapeutic effect with dosing intervals of up to six months.

Initial clinical trials were promising, with a pivotal placebo-controlled study (C-98-03) demonstrating statistically significant efficacy in stabilizing vision and inhibiting lesion growth in patients with wet AMD. However, a subsequent large-scale Phase III trial (C-01-99) comparing Anecortave Acetate to the then-standard photodynamic therapy (PDT) failed to establish non-inferiority, an outcome confounded by procedural variables such as drug reflux. A strategic pivot to a preventative indication—investigating whether the drug could halt the progression from dry to wet AMD in the massive Anecortave Acetate Risk-Reduction Trial (AART)—ultimately failed, with an interim analysis showing no clinical benefit.

In parallel, Anecortave Acetate was explored for its potential to lower intraocular pressure (IOP) in glaucoma, where it showed promising early results. Despite this, the entire development program was terminated between 2008 and 2009. The discontinuation was not primarily due to safety concerns but was a consequence of its modest clinical efficacy being eclipsed by the revolutionary success of a new class of biologics—the anti-Vascular Endothelial Growth Factor (VEGF) agents—which fundamentally reset the standard of care for wet AMD from vision stabilization to vision improvement. This report details the complete story of Anecortave, from its rational chemical design and unique pharmacology to its complex clinical trial history and ultimate withdrawal, serving as a salient case study in pharmaceutical development within a rapidly evolving therapeutic landscape.

Chemical Identity and Physicochemical Properties of Anecortave

A thorough understanding of Anecortave begins with its precise chemical identity and its relationship to the clinically investigated compound, Anecortave Acetate. The molecule specified by CAS Number 10184-70-0 and DrugBank ID DB12081 is Anecortave, which functions as the active drug moiety.[1] However, the vast majority of preclinical and clinical research was conducted using its prodrug, Anecortave Acetate (CAS Number 7753-60-8; DrugBank ID DB05288).[3] Anecortave Acetate is rapidly hydrolyzed in vivo to yield Anecortave, which is also referred to as anecortave desacetate or 21-Desacetyl Anecortave.[4]

Nomenclature and Identifiers

Anecortave is known by several chemical names and synonyms that reflect its structure and origin as a steroid derivative and investigational compound.

• Generic Name: Anecortave [1]
• Systematic (IUPAC) Name: (8S,10S,13S,14S,17R)-17-hydroxy-17-(2-hydroxyacetyl)-10,13-dimethyl-2,6,7,8,12,14,15,16-octahydro-1H-cyclopenta[a]phenanthren-3-one [2]
• CAS Number: 10184-70-0 [1]
• DrugBank ID: DB12081 [1]
• FDA UNII: R5Y8O51589 [1]
• Synonyms: 21-Desacetyl Anecortave, 17-Desacetyl Anecortave, AL 4940, AL-4940, 9(11)-Dehydrocortisol, 17,21-Dihydroxypregna-4,9(11)-diene-3,20-dione, Hydrocortisone Impurity 38 [1]

Structural and Molecular Data

Anecortave possesses a tetracyclic steroid core derived from a pregnane skeleton. Its structure is closely related to cortisol but features critical modifications designed to eliminate glucocorticoid activity.[3] Specifically, it is derived from cortisol by the removal of the 11-beta hydroxyl group and the formation of a double bond between carbons 9 and 11.[3] This structural re-engineering is fundamental to its unique pharmacological profile.

• Molecular Formula: C21​H28​O4​ [1]
• Molecular Weight: Average: 344.45 g/mol; Monoisotopic: 344.198759382 g/mol [1]
• Chemical Identifiers:
• InChIKey: BCFCRXOJOFDUMZ-ONKRVSLGSA-N [1]
• Canonical SMILES: CC12CCC(=O)C=C1CCC3C2=CCC4(C3CCC4(C(=O)CO)O)C [2]

Chemical Taxonomy and Classification

Anecortave is classified within the chemical taxonomy as a steroid. Its specific functional groups place it into several more detailed categories. According to the Classyfire system, it is described as a 21-hydroxysteroid, defined as a steroid carrying a hydroxyl group at the C21 position of the steroid backbone.[1] It belongs to the kingdom of organic compounds and the superclass of lipids and lipid-like molecules.[1] Its structure also contains a ketone at the C3 position (3-oxosteroid) and a ketone at the C20 position (20-oxosteroid), with hydroxyl groups at C17 and C21.[1]

The table below consolidates the key chemical and physical properties of Anecortave.

Table 1: Chemical and Physical Properties of Anecortave (DB12081)

Property	Value	Source(s)
Generic Name	Anecortave	1
CAS Number	10184-70-0	1
DrugBank ID	DB12081	1
Molecular Formula	C21​H28​O4​	1
Average Molecular Weight	344.45 g/mol	2
Monoisotopic Weight	344.198759382 g/mol	1
IUPAC Name	(8S,10S,13S,14S,17R)-17-hydroxy-17-(2-hydroxyacetyl)-10,13-dimethyl-2,6,7,8,12,14,15,16-octahydro-1H-cyclopenta[a]phenanthren-3-one	2
InChIKey	BCFCRXOJOFDUMZ-ONKRVSLGSA-N	1
Canonical SMILES	CC12CCC(=O)C=C1CCC3C2=CCC4(C3CCC4(C(=O)CO)O)C	2
Physical Form	Solid (Off-White to Light Beige)	9
Melting Point	231-233 °C	9
Predicted Water Solubility	0.0334 mg/mL	1
Predicted logP	2.98	1
Predicted pKa (Acidic)	12.58	1

Pharmacology and Mechanism of Action

The pharmacological innovation of Anecortave Acetate lies in its classification as an angiostatic cortisene, a compound class defined by the deliberate separation of anti-angiogenic properties from the hormonal activities inherent to its corticosteroid precursor. This was achieved through targeted chemical modifications, resulting in a molecule with a novel and broad-based mechanism of action.

Classification: Angiostatic Cortisene

Anecortave Acetate is the prototypical angiostatic cortisene, a term coined to describe this new class of anti-angiogenic agents.[12] It is a synthetic analog of cortisol acetate, but the removal of the 11β-hydroxyl group and the creation of a double bond between carbons 9 and 11 effectively abolishes its ability to bind to and activate glucocorticoid receptors.[3] Consequently, it is devoid of the anti-inflammatory, immunosuppressive, and side-effect-inducing properties of traditional glucocorticoids, such as cataractogenesis and elevation of intraocular pressure.[3] This feat of medicinal chemistry allowed for the exploitation of the steroid backbone's angiostatic potential without undesirable hormonal effects.[12]

Multi-Target, Downstream Mechanism

A key differentiator of Anecortave's mechanism was its broad-based action on multiple, downstream events in the angiogenic cascade.[10] At the time of its development, many emerging therapies, particularly the anti-VEGF agents, were highly specific, targeting a single pro-angiogenic growth factor. The therapeutic hypothesis for Anecortave was that a multi-factorial inhibitor would be more robust and less susceptible to bypass mechanisms. By acting "downstream and independent of the initiating angiogenic stimuli," it was designed to inhibit neovascularization regardless of the specific growth factor or trigger that initiated the process.[10]

Preclinical studies elucidated several specific pathways modulated by Anecortave:

• Inhibition of Cell Migration and Protease Expression: It functions by inhibiting the migration of endothelial cells and decreasing the expression of extracellular proteases, such as matrix metalloproteinases (MMPs).[10] These enzymes are essential for degrading the basement membrane and extracellular matrix, a critical prerequisite for endothelial cells to move and form new vessel tubes.[18]
• Down-regulation of Growth Factors: Preclinical evidence showed that Anecortave Acetate also down-regulates the expression and production of key pro-angiogenic factors, including Vascular Endothelial Growth Factor (VEGF) and Insulin-like Growth Factor 1 (IGF-1).[5]

This broad-based approach represented a compelling scientific strategy. However, the clinical development of Anecortave Acetate became a real-world test of this "broad-based" pharmacological philosophy against the "highly targeted" philosophy of anti-VEGF agents. While logically sound, the diffuse, modulatory effect of Anecortave proved less potent in a clinical setting than the direct, powerful blockade of the VEGF pathway, which was later identified as the overwhelmingly dominant pathological driver in wet AMD.[19] The eventual triumph of anti-VEGF therapies demonstrated that in this specific disease, a highly targeted approach yielded a more profound clinical benefit.

Receptor-Independent Activity

Further distinguishing it from conventional steroids, the angiostatic activity of Anecortave does not appear to be mediated through any of the commonly known pharmacological receptors.[10] This suggests a novel intracellular mechanism, potentially involving direct interaction with components of the cellular machinery responsible for migration and matrix remodeling. This receptor-independent action reinforces its unique classification and separates it from traditional hormone-receptor-mediated signaling pathways.

Pharmacokinetics and Metabolism

The clinical application of Anecortave Acetate was critically dependent on a specialized pharmacokinetic profile, centered around a novel drug delivery system designed to provide sustained, localized drug levels to the posterior segment of the eye while minimizing systemic exposure.

Administration Route: Posterior Juxtascleral Depot (PJD)

Early investigations determined that conventional administration routes were unsuitable for Anecortave Acetate. Oral administration was impractical due to rapid systemic metabolism, while topical and subconjunctival injections failed to achieve therapeutic concentrations in the target tissues of the retina and choroid.[5] Intravitreal injections, while effective in animal models, carried significant risks such as endophthalmitis and retinal detachment.[5]

To overcome these challenges, Alcon developed a novel delivery method: the posterior juxtascleral depot (PJD).[3] This procedure involves:

1. A small incision in the conjunctiva and Tenon's capsule.
2. Insertion of a specially designed, blunt-tipped, curved cannula that follows the curvature of the globe, allowing it to reach the posterior pole of the eye without perforation.[5]
3. Injection of the Anecortave Acetate suspension into the juxtascleral space, forming a depot directly over the macula.[16]

This PJD system was a cornerstone of the drug's therapeutic proposition. The low solubility of the compound allowed the depot to act as a slow-release reservoir, providing sustained therapeutic drug concentrations to the choroid and retina for up to six months from a single administration.[16] This offered a significant potential advantage over other therapies requiring more frequent injections, thereby reducing treatment burden and improving patient compliance.[3]

However, this innovative delivery system also introduced a critical variable that would ultimately confound clinical trial results. The technical precision required for the PJD procedure was high, and improper administration could lead to reflux of the drug suspension from the depot site.[5] Pharmacokinetic studies confirmed that patients who experienced reflux had lower plasma concentrations of the active metabolite.[24] As detailed in subsequent sections, post-hoc analyses of the pivotal C-01-99 trial revealed that clinical efficacy was diminished in patients with observed reflux, demonstrating that the success of this novel drug was inextricably linked to the practical challenges of its delivery system.[21]

Metabolism and Systemic Exposure

Anecortave Acetate is a prodrug that undergoes rapid and extensive metabolism.

• Activation: Upon administration, it is quickly hydrolyzed by ubiquitous esterases in ocular tissues and plasma to its pharmacologically active metabolite, Anecortave (also known as anecortave desacetate).[5]
• Further Metabolism and Elimination: Anecortave is subsequently metabolized via reduction to one major and several minor inactive products. These metabolites are then conjugated with glucuronic acid and circulate as glucuronides before elimination.[23]
• Systemic Exposure: Following a 15 mg PJD administration in AMD patients, quantifiable plasma concentrations of Anecortave and its metabolites were low and transient, typically detectable for only about two weeks.[5] Importantly, pharmacokinetic studies involving repeated PJD administrations at six-month intervals showed no evidence of systemic accumulation of either the parent drug or its metabolites, indicating that the elimination pathways were not saturated.[5] This favorable systemic safety profile was a key attribute of the localized PJD delivery approach.

Clinical Development in Age-Related Macular Degeneration (AMD)

The clinical development program for Anecortave Acetate in AMD was extensive, progressing from a promising proof-of-concept trial to large-scale comparative and preventative studies. This journey ultimately defined the drug's fate, as it unfolded against the backdrop of a revolutionary shift in the standard of care for AMD.

5.1. The C-98-03 Monotherapy Trial (Phase II/III)

The foundation for the Anecortave Acetate program was laid by the C-98-03 trial, a 24-month, randomized, double-masked, placebo-controlled study designed to establish its safety and efficacy as a monotherapy for exudative AMD.[5] The trial enrolled 128 patients with subfoveal choroidal neovascularization (CNV) who were randomized to receive PJD administrations of Anecortave Acetate (3 mg, 15 mg, or 30 mg) or a placebo every six months.[18]

The results were highly encouraging and established clinical proof-of-concept:

• Efficacy: The 15 mg dose emerged as the most effective. At the 24-month primary endpoint, Anecortave Acetate 15 mg was statistically superior to placebo in preserving vision (defined as losing less than 3 lines, or 15 letters, of visual acuity). In the 15 mg group, 73% of patients maintained their vision, compared to only 47% in the placebo group (p≤0.05).[15]
• Vision Loss Prevention: The treatment also significantly reduced the risk of severe vision loss (losing ≥6 lines). This outcome occurred in only 6% of patients in the 15 mg group versus 23% of patients in the placebo group (p≤0.05).[18]
• Lesion Growth Inhibition: Anecortave Acetate 15 mg demonstrated a statistically significant ability to inhibit the growth of the classic CNV component of lesions compared to placebo (p≤0.05).[18]

The C-98-03 trial was a clear success, demonstrating that Anecortave Acetate 15 mg was a safe and effective primary therapy for exudative AMD, superior to placebo in both maintaining vision and suppressing lesion progression.[5]

5.2. The C-01-99 Comparative Trial (Phase III)

Building on the positive results of C-98-03, Alcon initiated the C-01-99 trial, a large-scale, 24-month, active-controlled study designed to compare Anecortave Acetate 15 mg against the existing standard of care, photodynamic therapy (PDT) with verteporfin (Visudyne).[5] This non-inferiority trial enrolled 530 patients with predominantly classic subfoveal CNV. Patients were randomized to receive either Anecortave Acetate via PJD every six months (plus sham PDT every three months) or active PDT every three months (plus sham PJD every six months).[5]

The results of this pivotal trial were ambiguous and ultimately disappointing:

• Primary Endpoint: The study failed to meet its primary endpoint of demonstrating non-inferiority at 12 months. The percentage of patients maintaining vision was 45% in the Anecortave Acetate group versus 49% in the PDT group (p=0.43).[18]
• Clinical Equivalence: Over the full 24 months, the two treatments were considered clinically equivalent, with the mean visual acuity between the groups differing by only a few letters at any time point.[14]

The trial's outcome was significantly complicated by the confounding factors previously discussed. Post-hoc analyses showed that when patients who experienced drug reflux were excluded, the vision preservation rate in the Anecortave Acetate arm improved to 57%.[21] Furthermore, the study population had unusually small and aggressive lesions, which may have limited the efficacy of both therapies.[18] While technically showing equivalence to the standard of care, this result was not strong enough to support a compelling case for regulatory approval, especially as a new, more effective class of drugs was emerging.

5.3. The Anecortave Acetate Risk-Reduction Trial (AART; C-02-60)

In a major strategic pivot, Alcon initiated the Anecortave Acetate Risk-Reduction Trial (AART), a massive, multi-year, international study designed to evaluate a preventative indication.[27] The primary objective was to determine if Anecortave Acetate (15 mg or 30 mg), administered every six months, could reduce the risk of progression from high-risk non-exudative ("dry") AMD to sight-threatening exudative ("wet") AMD when compared to a sham procedure.[22] The trial began in 2004 and ultimately enrolled over 2,500 patients.[22]

This ambitious trial ended in a definitive failure that sealed the fate of the AMD program. In July 2008, Alcon announced it was terminating the AART study and the entire AMD development program for Anecortave Acetate.[3] The decision was based on a planned interim analysis of data from 2,546 patients at the 24-month time point, which concluded that Anecortave Acetate demonstrated

no effect on either the primary or secondary endpoints.[30] It did not arrest the progression from dry to wet AMD.

The table below summarizes the key clinical trials that defined the development trajectory of Anecortave Acetate in AMD.

Table 2: Summary of Key Clinical Trials of Anecortave Acetate in Age-Related Macular Degeneration

Trial ID	Phase	Design	Patient Population (n)	Treatment Arms	Primary Endpoint	Key Efficacy Outcome
C-98-03	II/III	Randomized, Placebo-Controlled, Double-Masked	Exudative AMD (128)	Anecortave Acetate (3, 15, 30 mg) vs. Placebo	Mean change in visual acuity at 24 months	15 mg dose superior to placebo; 73% maintained vision vs. 47% for placebo (p≤0.05) 18
C-01-99	III	Randomized, Active-Controlled, Double-Masked	Predominantly Classic Exudative AMD (530)	Anecortave Acetate 15 mg vs. PDT with Verteporfin	Non-inferiority in vision maintenance at 12 months	Failed to meet primary endpoint; 45% maintained vision vs. 49% for PDT (p=0.43) 18
AART (C-02-60)	III	Randomized, Sham-Controlled, Double-Masked	High-Risk Dry AMD (>2,500)	Anecortave Acetate (15, 30 mg) vs. Sham	Incidence of sight-threatening CNV	Terminated; interim analysis showed no effect on preventing progression to wet AMD 30

The clinical journey of Anecortave Acetate illustrates the critical impact of a shifting therapeutic landscape. It was developed in an era where "vision stabilization" was the primary goal of AMD therapy, a standard set by PDT.[19] The C-98-03 trial showed it could meet this standard effectively. However, during the execution of the C-01-99 and AART trials, anti-VEGF agents like ranibizumab and bevacizumab emerged, demonstrating an unprecedented ability to not only stabilize but actively

improve vision in a significant portion of patients.[19] This paradigm shift raised the bar for efficacy so dramatically that Anecortave Acetate's more modest benefit of being "as good as PDT" was no longer clinically or commercially viable.[19]

Clinical Investigation in Glaucoma and Ocular Hypertension

As the prospects for Anecortave Acetate in AMD began to wane, Alcon initiated a second line of investigation, exploring its potential utility in lowering intraocular pressure (IOP) for the treatment of glaucoma and ocular hypertension.[3] This represented an attempt to salvage a promising molecule by repurposing it for a different ophthalmic indication.

Rationale

The rationale for this investigation was novel, as angiostatic agents are not typically associated with IOP modulation. The research was based on the hypothesis that Anecortave Acetate, administered as an anterior juxtascleral depot (AJD) in the sub-Tenon's space, might have a direct effect on the aqueous outflow pathways, such as the trabecular meshwork.[19]

Steroid-Induced Ocular Hypertension

The first clinical evidence for an IOP-lowering effect came from a small, uncontrolled case series published in 2009.[34] The study included eight eyes from seven patients with severe, medically uncontrolled ocular hypertension caused by prior injections of the corticosteroid triamcinolone acetonide. These patients received a 24 mg AJD of Anecortave Acetate.

The results were striking:

• The mean baseline IOP was extremely high at 39.9 mm Hg.
• After one week, the mean IOP decreased by 12 mm Hg (29%, p=0.005).
• By one month, the mean IOP had decreased by 14.1 mm Hg (34.5%, p=0.003) from baseline.[34]

This pilot study provided the first human evidence that Anecortave Acetate could substantially lower IOP, particularly in the challenging context of steroid-induced glaucoma.[33]

Open-Angle Glaucoma

These promising findings led to more formal, controlled trials. Alcon conducted a randomized, placebo-controlled, proof-of-concept study in 89 patients with open-angle glaucoma.[35] Patients received a single AJD of Anecortave Acetate (7.5 mg or 15 mg) or a vehicle control. At the pre-defined 3-month primary efficacy endpoint, both the 7.5 mg and 15 mg doses demonstrated a statistically significant lower mean IOP compared to the vehicle (

p<0.05).[35]

A subsequent, larger Phase II safety and efficacy study (NCT00691717) was initiated to evaluate higher doses (up to 60 mg) in patients with open-angle glaucoma or ocular hypertension.[1]

Discontinuation

Despite the positive and statistically significant results from these early-stage glaucoma trials, Alcon announced in 2009 that it was terminating the development of Anecortave Acetate for reducing IOP.[3] This decision was likely not a reflection of scientific failure in the glaucoma indication itself, but rather a broader, portfolio-level business decision to cease all investment in the Anecortave platform after its definitive and costly failure in the much larger AMD market. The promising IOP-lowering data suggested a novel biological mechanism, but the termination of the program left this mechanism unexplored and represented a lost opportunity to develop a potentially new class of glaucoma therapy.

Safety Profile and Drug Interactions

Throughout its extensive clinical development in both AMD and glaucoma, Anecortave Acetate, along with its PJD and AJD administration procedures, demonstrated a favorable safety profile.

Overall Safety Profile

Across multiple large trials involving thousands of patients, the drug was consistently found to be safe and well-tolerated.[15] A key success of its design was the absence of typical corticosteroid-related adverse events. Clinical trials confirmed that, unlike traditional steroids, Anecortave Acetate did not cause clinically relevant increases in IOP or accelerate cataract formation.[5] An independent safety committee that reviewed the data from the AMD trials identified no clinically relevant safety issues related to either the medication or the administration procedure.[5]

Common Ocular Adverse Events (Procedure-Related)

The majority of reported adverse events were ocular, generally mild, transient, and considered related to the juxtascleral injection procedure rather than the drug itself.[5] The most common of these events included:

• Ptosis (drooping eyelid)
• Ocular pain or discomfort
• Subconjunctival hemorrhage
• Ocular pruritus (itching)
• Hyperemia (redness)
• Foreign body sensation [18]

These events occurred at similar frequencies in both active treatment and sham procedure groups, underscoring their link to the physical administration process.[18]

Drug Interactions

The documented drug interactions for Anecortave are largely theoretical, based on its chemical properties and pharmacological class, rather than on observed clinical events. The primary risks identified are summarized in Table 3.

Table 3: Documented Drug Interactions with Anecortave

Risk / Effect	Interacting Drug Class	Specific Examples	Source(s)
Increased risk of Methemoglobinemia	Local Anesthetics & Various Agents	Articaine, Benzocaine, Lidocaine, Prilocaine, Bupivacaine, Capsaicin, Cocaine, Phenol	1
Increased risk of Jaw Osteonecrosis & Anti-angiogenesis	Bisphosphonates	Alendronic acid, Clodronic acid, Etidronic acid, Risedronic acid, Zoledronic acid	1
Increased risk of Thrombosis	Erythropoiesis-Stimulating Agents	Darbepoetin alfa, Erythropoietin	1

Regulatory History and Discontinuation

The regulatory journey of Anecortave Acetate was characterized by initial optimism, reflected in its expedited review status, followed by significant setbacks that, combined with a shifting competitive landscape, ultimately led to the termination of its development.

Regulatory Pathway

Recognizing the significant unmet need for effective wet AMD treatments at the time, the U.S. Food and Drug Administration (FDA) granted Anecortave Acetate "Fast Track" designation.[3] It was also accepted into the FDA's new Pilot 1 Continuous Marketing Application (CMA) program, which allowed Alcon to submit its New Drug Application (NDA) in separate, reviewable units as they were completed.[3] The final unit of the NDA was submitted to the FDA in early 2005, and a Marketing Authorisation Application was submitted to the European Medicines Agency (EMEA) in late 2004.[39]

Regulatory Setbacks

The first major hurdle appeared in May 2005, when Alcon received an "approvable letter" from the FDA, rather than a full approval.[40] The letter indicated that final approval for the wet AMD indication would be contingent on the completion of an additional clinical study.[19] This requirement likely stemmed from the ambiguous results of the C-01-99 comparative trial and the rapidly rising efficacy bar being set by emerging anti-VEGF therapies.

The regulatory challenges were mirrored in Europe. In March 2006, Alcon formally withdrew its application from the EMEA, stating that the decision was based on its research, development, and marketing strategies, and after learning the European agency would also require new clinical data.[19]

By September 2007, Alcon publicly announced that it had no immediate plans to conduct the additional trial requested by the FDA. The company cited the extreme difficulty of recruiting patients for such a study, given the widespread availability and superior efficacy of newly approved treatments for wet AMD.[3]

Termination of Development

The final decisions to halt the program followed the definitive failure of the AART study.

• July 2008: Following the negative interim analysis of the AART, which showed no benefit in preventing the progression of AMD, Alcon officially announced the termination of the entire development program for Anecortave Acetate in AMD.[3]
• 2009: The company announced the termination of the parallel development program for glaucoma.[3]

As of 2010, all development activities for Anecortave Acetate had ceased, and the drug has not been brought to market for any indication.[3]

Concluding Analysis: A Promising Agent in a Revolutionary Era

The history of Anecortave and its prodrug, Anecortave Acetate, offers a compelling case study in the complexities and risks of pharmaceutical research and development. It is the story of a scientifically elegant and innovative compound that was ultimately rendered obsolete by a paradigm shift in its target therapeutic area.

Scientific Merit vs. Clinical Reality

From a medicinal chemistry and pharmacology perspective, Anecortave Acetate was a triumph of rational drug design. The successful engineering of a steroid derivative that retained potent anti-angiogenic activity while shedding its glucocorticoid properties was a significant achievement. Its broad-based, downstream mechanism of action and its novel, long-acting PJD delivery system were logical and well-conceived strategies to address the complex pathology of wet AMD. The drug demonstrated a strong safety profile and clear biological activity in both preclinical models and human clinical trials.

The Impact of a Paradigm Shift

The ultimate failure of Anecortave Acetate was less a reflection of its own scientific deficiencies and more a consequence of extraordinary bad timing. Its development coincided precisely with the discovery and clinical validation of anti-VEGF biologics like ranibizumab (Lucentis), bevacizumab (Avastin), and later, aflibercept (Eylea).[19] These agents produced results that were not just statistically significant but clinically transformative.

The therapeutic goalpost for wet AMD shifted almost overnight from "slowing vision loss"—an endpoint Anecortave Acetate could meet—to "improving vision," a standard it could not.[19] Anecortave Acetate was designed and tested against an older standard of care (PDT), and by the time its pivotal trial data were available, that standard was already obsolete. The FDA's request for an additional trial in 2005 was an implicit acknowledgment that the drug now had to prove its worth against a much higher bar, a challenge its developer rightly concluded was insurmountable.

Lessons Learned

The story of Anecortave provides several critical lessons. It demonstrates that even a well-designed drug with a novel mechanism and a good safety profile can fail if it is outpaced by disruptive innovation. Success in drug development requires not only demonstrating efficacy against a placebo or non-inferiority to a current standard but also delivering a clinically meaningful benefit that can compete in a dynamic and forward-moving field. It also highlights the critical interplay between a drug and its delivery system, where procedural challenges can undermine the ability to demonstrate a compound's true efficacy.

Finally, while the commercial journey of Anecortave is over, it leaves behind intriguing scientific questions. The molecular basis for its broad-based angiostatic activity and, perhaps more compellingly, its non-glucocorticoid-mediated ability to lower intraocular pressure, remain areas of scientific interest. The data from its discontinued glaucoma program suggest a novel biological pathway for regulating IOP that, while commercially abandoned, may yet hold value for future research.

Works cited

1. Anecortave: Uses, Interactions, Mechanism of Action | DrugBank ..., accessed August 29, 2025, https://go.drugbank.com/drugs/DB12081
2. CAS 10184-70-0 21-Desacetyl Anecortave - Alfa Chemistry, accessed August 29, 2025, https://www.alfa-chemistry.com/product/21-desacetyl-anecortave-cas-10184-70-0-53676.html
3. Anecortave acetate - Wikipedia, accessed August 29, 2025, https://en.wikipedia.org/wiki/Anecortave_acetate
4. CAS No : 10184-70-0 | Product Name : 21-Desacetyl Anecortave | Pharmaffiliates, accessed August 29, 2025, https://www.pharmaffiliates.com/en/10184-70-0-21-desacetyl-anecortave-pa012701000.html
5. Retaane: Targeting Multiple Factors - Review of Ophthalmology, accessed August 29, 2025, https://www.reviewofophthalmology.com/article/retaane-targeting-multiple-factors
6. 21-Desacetyl Anecortave - LGC Standards, accessed August 29, 2025, https://www.lgcstandards.com/BN/en/21-Desacetyl-Anecortave/p/TRC-D288340
7. Browse Substances, accessed August 29, 2025, https://gsrs-dev-public.ncats.io/ginas/app/ui/browse-substance?search=root_codes_comments:%22anecortave%22
8. Browse Substances, accessed August 29, 2025, https://gsrs-dev-public.ncats.io/ginas/app/ui/browse-substance?search=root_codes_comments:%22OCULAR%20VASCULAR%20DISORDER%20AGENTS%22
9. ANECORTAVE ACETATE RELATED COMPOUND A (20 MG) (9(11 )-DEHYDROCORTISOL) | 10184-70-0 - ChemicalBook, accessed August 29, 2025, https://www.chemicalbook.com/ChemicalProductProperty_EN_CB0501628.htm
10. Anecortave acetate: Uses, Interactions, Mechanism of Action | DrugBank Online, accessed August 29, 2025, https://go.drugbank.com/drugs/DB05288
11. 10184-70-0 | MFCD00271920 | Anecortave - Aaronchem, accessed August 29, 2025, https://www.aaronchem.com/10184-70-0
12. Mechanism of action of the angiostatic cortisene anecortave acetate, accessed August 29, 2025, https://pubmed.ncbi.nlm.nih.gov/17240253/
13. Treatment of Steroid-Induced Elevated Intraocular Pressure with Anecortave Acetate: A Randomized Clinical Trial - PMC - PubMed Central, accessed August 29, 2025, https://pmc.ncbi.nlm.nih.gov/articles/PMC3505827/
14. Anecortave acetate found safe, effective in AMD, accessed August 29, 2025, https://www.ophthalmologytimes.com/view/anecortave-acetate-found-safe-effective-amd
15. Anecortave acetate in the treatment of age-related macular degeneration | CIA, accessed August 29, 2025, https://www.dovepress.com/anecortave-acetate-in-the-treatment-of-age-related-macular-degeneratio-peer-reviewed-fulltext-article-CIA
16. Anecortave Acetate: Treatment for Age-Related Macular Degeneration | Retinal Physician, accessed August 29, 2025, https://www.retinalphysician.com/issues/2004/august/anecortave-acetate-treatment-for-age-related-macular-degeneration/
17. Anecortave Acetate - Inxight Drugs, accessed August 29, 2025, https://drugs.ncats.io/drug/Y0PC411K4T
18. Anecortave acetate in the treatment of age-related macular ..., accessed August 29, 2025, https://pmc.ncbi.nlm.nih.gov/articles/PMC2695182/
19. Alcon stops FDA approval for wet AMD treatment - Ophthalmology Times, accessed August 29, 2025, https://www.ophthalmologytimes.com/view/alcon-stops-fda-approval-wet-amd-treatment
20. Comparison of aflibercept, bevacizumab, and ranibizumab for treatment of diabetic macular edema: Extrapolation of data to clinical practice - Johns Hopkins University, accessed August 29, 2025, https://pure.johnshopkins.edu/en/publications/comparison-of-aflibercept-bevacizumab-and-ranibizumab-for-treatme
21. Anecortave Acetate (Retaane) - Medical Clinical Policy Bulletins - Aetna, accessed August 29, 2025, https://www.aetna.com/cpb/medical/data/700_799/0706.html
22. AART focus is on prevention of sight-threatening CNV - Ophthalmology Times, accessed August 29, 2025, https://www.ophthalmologytimes.com/view/aart-focus-prevention-sight-threatening-cnv
23. Pharmacokinetics and metabolism of anecortave acetate in animals ..., accessed August 29, 2025, https://pubmed.ncbi.nlm.nih.gov/17240257/
24. Clinical Outcomes of Two Open–Label Pharmacokinetic Studies With Anecortave Acetate in Patients With Exudative Age–Related Macular Degeneration (AMD) | IOVS, accessed August 29, 2025, https://iovs.arvojournals.org/article.aspx?articleid=2400854
25. Anecortave acetate for the treatment of subfoveal choroidal neovascularization secondary to age-related macular degeneration - PubMed, accessed August 29, 2025, https://pubmed.ncbi.nlm.nih.gov/16001382/
26. Current Trials Lexington | Research Ashland - Retina Associates of Kentucky, accessed August 29, 2025, https://www.retinaky.com/research/
27. AART to assess use of anecortave acetate in preventing progression to wet AMD, accessed August 29, 2025, https://www.ophthalmologytimes.com/view/aart-assess-use-anecortave-acetate-preventing-progression-wet-amd
28. EU Clinical Trials Register, accessed August 29, 2025, https://www.clinicaltrialsregister.eu/ctr-search/trial/2005-001598-93/DK/
29. Anecortave Acetate Treatment of "Dry" AMD to Reduce Risk of Progression to "Wet" AMD – The Anecortave Acetate Risk Reduction Trial (AART) | IOVS, accessed August 29, 2025, https://iovs.arvojournals.org/article.aspx?articleid=2408676
30. Alcon Laboratories Ends Macular Degeneration Drug Program | Fierce Biotech, accessed August 29, 2025, https://www.fiercebiotech.com/biotech/alcon-laboratories-ends-macular-degeneration-drug-program
31. Alcon axes eye program - Fierce Biotech, accessed August 29, 2025, https://www.fiercebiotech.com/biotech/alcon-axes-eye-program
32. Comparison of Anti-VEGF Treatments for Wet AMD - American Academy of Ophthalmology, accessed August 29, 2025, https://www.aao.org/eye-health/diseases/avastin-eylea-lucentis-difference
33. Anecortave acetate lowers IOP substantially in some eyes with steroid-related ocular hypertension - American Academy of Ophthalmology, accessed August 29, 2025, https://www.aao.org/education/editors-choice/anecortave-acetate-lowers-iop-substantially-in-som
34. Reduction of intraocular pressure with anecortave acetate in eyes ..., accessed August 29, 2025, https://pubmed.ncbi.nlm.nih.gov/19204235/
35. Alcon Presents Clinical Trial Data On Anecortave Acetate For Glaucoma, accessed August 29, 2025, https://www.ophthalmologyweb.com/1315-News/31500-Alcon-Presents-Clinical-Trial-Data-On-Anecortave-Acetate-For-Glaucoma/
36. Anecortave Acetate Safety in Patients With Open-Angle Glaucoma or Ocular Hypertension, accessed August 29, 2025, https://clinicaltrials.gov/study/NCT00691717
37. Anecortave Acetate Safety in Patients With Open-Angle Glaucoma or Ocular Hypertension, accessed August 29, 2025, https://www.clinicaltrials.gov/study/NCT00691717
38. www.sec.gov, accessed August 29, 2025, https://www.sec.gov/Archives/edgar/data/1167379/000116737904000022/acl6kprretaaneex991.htm
39. Alcon submits final NDA for anecortave acetate - Ophthalmology Times, accessed August 29, 2025, https://www.ophthalmologytimes.com/view/alcon-submits-final-nda-anecortave-acetate
40. Retaane (anecortave acetate): What is it and is it FDA approved? - Drugs.com, accessed August 29, 2025, https://www.drugs.com/history/retaane.html
41. Press release Alcon Laboratories withdraws its application for RETAANE - EMA, accessed August 29, 2025, https://www.ema.europa.eu/en/documents/press-release/alcon-laboratories-withdraws-its-application-retaane_en.pdf
42. Exhibit 99.1 For immediate release Alcon Receives FDA Decision on RETAANE® Suspension for Wet AMD HUENENBERG, Switzerland – - SEC.gov, accessed August 29, 2025, https://www.sec.gov/Archives/edgar/data/1167379/000116737907000093/acl6k07retaaneex991.pdf
43. Name of Policy: Conjunctival Incision with Posterior ... - AAPC, accessed August 29, 2025, https://www.aapc.com/codes/webroot/upload/general_pages_docs/document/2541.pdf
44. Aflibercept – How does it compare with other Anti-VEGF Drugs? - Austin Publishing Group, accessed August 29, 2025, https://austinpublishinggroup.com/clinical-ophthalmology/fulltext/ajco-v1-id1016.php