EyeBio Phase 1/2 results

February 22, 2024

This is not investment advice. We used AI and automated software tools for most of this research. A human formatted the charts based on data / analysis from the software, prompted the AI to do some editing, and did some light manual editing. We did some fact checking but cannot guarantee the accuracy of everything in the article. We do not have a position in or a relationship with the company.

Note: this is an update of a prior analysis of the company. This update only covers the clinical data announced in February 2024; for the full overview of the company, click here.

Phase 1/2 results

The AMARONE trial by EyeBio, a Phase 1b/2a study evaluating Restoret for the treatment of treatment-naïve diabetic macular edema (DME) and neovascular age-related macular degeneration (NVAMD), has reported positive 12-week outcomes. The key findings from the trial can be summarized as follows:

Well-Tolerated Treatment: Restoret was well-tolerated among participants, with no reported drug-related adverse events, serious adverse events, or intraocular inflammation. This suggests a favorable safety profile for the drug in early clinical evaluation.

Visual Acuity Improvement: Patients with DME treated with Restoret monotherapy showed a significant mean improvement in best-corrected visual acuity (BCVA), gaining 11.2 letters. This indicates a meaningful improvement in vision for these patients.

For reference, below is a summary of BCVA changes in key Phase 3 studies in wet AMD and DME of comparable agents:

Select wet AMD Phase 3 studies

Study Name	Mean Improvement in BCVA (Letters)	Time (in weeks) at BCVA Assessment
VIEW 1 & VIEW 2 (Eylea)	Approximately 8-11	52
MARINA (Lucentis)	Approximately 7-10	52
ANCHOR (Lucentis)	Approximately 11-15	52
TENAYA & LUCERNE (Vabysmo)	Approximately 5-6	48-52
HAWK & HARRIER (Beovu)	Approximately 6-10	48

Select Diabetic Macular Edema Phase 3 studies

Study Name	Mean Improvement in BCVA Letters (Brolucizumab vs. Aflibercept)	Time (in weeks) at BCVA Assessment
VIVID-DME (Eylea)	10.7	52
VISTA-DME (Eylea)	12.5	52
RISE (Lucentis)	10.9	24
RIDE (Lucentis)	12.5	24
Protocol T (Eylea vs. Lucentis vs. Avastin)	Eylea: 13.3, Lucentis: 11.7	52
KESTREL (Brolucizumab)	+9.2 (Brolucizumab 6 mg) vs +10.5 (Aflibercept)	52
KITE (Brolucizumab)	+10.6 (Brolucizumab 6 mg) vs +9.4 (Aflibercept)	52

Anatomic Improvement: There was a substantial mean reduction in retinal thickness (-143 microns) among DME patients, as measured by optical coherence tomography (OCT). This reduction in retinal thickness is indicative of anatomic improvement in the eye, addressing the swelling associated with DME .

Efficacy in NVAMD: Similar positive outcomes were observed in a smaller cohort of NVAMD patients (n=5), who were treated with Restoret in combination with aflibercept. This suggests potential efficacy of Restoret in treating NVAMD, either as monotherapy or in combination with existing anti-VEGF therapies.

Innovative Mechanism: The trial represents the first clinical use of a Wnt pathway agonist in retinal disease, marking a significant step in exploring alternative therapeutic mechanisms beyond VEGF inhibition for exudative retinal diseases .

Trial Design and Conduct: The trial involved a multi-center, two-part design, including an open-label multiple ascending dose safety study and a single-masked comparative safety and preliminary efficacy study. It tested four increasing doses of Restoret across different cohorts, with DME patients receiving monotherapy and NVAMD patients receiving combination therapy with aflibercept.

Data Integrity: The trial also highlighted the importance of quality control and data integrity, with corrections made to ensure the accuracy of the visual acuity measurements and overall data reliability.

In summary, the AMARONE trial's 12-week data demonstrate promising safety and efficacy of Restoret for the treatment of DME and NVAMD, showcasing its potential as a novel therapeutic option with a unique mechanism of action. While these early results are encouraging, further studies with larger patient populations and longer follow-up periods will be essential to fully establish the drug's clinical benefits and positioning within the treatment landscape for these conditions.

Approvability in wet AMD based on FDA guidance

Note: this applies to wet AMD only. FDA guidance for diabetic macular edema is not available

Based on the FDA's recent guidance for the development of drugs for the treatment of neovascular age-related macular degeneration (wet AMD), there are specific efficacy considerations and benchmarks that need to be met for approval. Here's how the observed Best Corrected Visual Acuity (BCVA) gain in the AMARONE trial aligns with this guidance:

• Statistically Significant Difference in BCVA: The guidance specifies that a novel therapy should demonstrate a statistically significant difference in mean BCVA of 15 or more letters at 9 months or later after the start of drug administration. The AMARONE trial reported a mean vision gain of 11.2 letters at 12 weeks, which is a promising result for an early-phase trial but does may not yet meet the FDA's specified benchmark for efficacy at 9 months. It's important to note that these results are at 12 weeks (approximately 3 months), which is earlier than the 9-month benchmark set by the FDA. Further, interpretation of FDA guidance may be subjective, and ultimate approvability will rely on data generated in Phase 3 studies as well as FDA’s judgment.
• Comparison to Control or Existing Therapies: The FDA guidance also mentions the importance of comparing the investigational drug's efficacy to a control group or existing therapies such as ranibizumab or aflibercept. In the specific benchmarks provided, it refers to the lower bound of the 95% confidence interval for the difference in BCVA between the investigational drug and control (ranibizumab or aflibercept) being not less than -4.5 letters at 9 months or later. The AMARONE trial does mention patients with NVAMD receiving Restoret in combination with aflibercept, but does not provide a direct comparison to a control group receiving only aflibercept or another standard therapy.
• Duration of Follow-Up: The FDA emphasizes the demonstration of efficacy at 9 months or later, which is beyond the 12-week (3-month) duration of the AMARONE trial. For the drug to align with FDA guidance, longer-term results demonstrating sustained or improved efficacy beyond the initial 12 weeks will be necessary.
• Adequacy of Clinical Trials: The guidance specifies the need for at least two adequate and well-controlled multicenter trials. The AMARONE trial is a first-in-human Phase 1b/2a trial, indicating that additional, larger Phase 3 trials will be required to fully assess the drug's safety and efficacy in line with FDA recommendations.

In summary, while the BCVA gain observed in the AMARONE trial is encouraging and suggests provides very early evidence of potential efficacy of Restoret for wet AMD , the data presented may not yet meet the FDA's efficacy benchmarks for approval. Specifically, the trial's duration, the magnitude of BCVA improvement, and the lack of comparison to a control group at the specified 9-month (or later) mark are key areas where additional data will be required to align with FDA guidance. Future trials will need to address these aspects, particularly focusing on longer-term efficacy and direct comparisons with existing therapies, to support a potential approval .

Potential market positioning based on data

Standard of Care for Wet AMD and DME

The current standard of care for neovascular age-related macular degeneration (wet AMD) and diabetic macular edema (DME) primarily involves anti-vascular endothelial growth factor (anti-VEGF) therapies. These include agents such as ranibizumab (Lucentis), aflibercept (Eylea), faricimab (Vabysmo), and brolucizumab (Beovu) for wet AMD, and similar agents for DME, with periodic intravitreal injections to control disease progression and improve vision. Despite the effectiveness of these treatments, there are notable limitations, including:

• Treatment Burden: Frequent intravitreal injections are required, leading to a high treatment burden for patients and healthcare systems.
• Variability in Response: Some patients exhibit suboptimal response to anti-VEGF therapies, experiencing limited visual acuity gains or requiring more frequent treatments.
• Long-term Efficacy and Safety: Concerns remain regarding the long-term efficacy and safety of continuous anti-VEGF therapy, including potential tachyphylaxis (diminishing response) and rare but serious adverse effects.

Unmet Clinical Need

Given these challenges, there is a significant unmet need for treatments that can offer:

• Reduced Treatment Frequency: Therapies that maintain efficacy with less frequent dosing could significantly reduce the treatment burden and improve patient adherence.
• Alternative Mechanisms of Action: Drugs that operate via different pathways, such as the Wnt pathway targeted by Restoret, may benefit patients who are non-responders or partially responsive to anti-VEGF treatments.
• Improved Safety Profile: Treatments with fewer or less severe side effects are always desirable, particularly for the elderly population predominantly affected by wet AMD and DME.

Market Opportunity for Restoret

If Restoret is approved, its market opportunity could be substantial, reflecting several factors:

• Broad Patient Population: Wet AMD and DME affect millions worldwide, with prevalence increasing as populations age. A new effective treatment could capture a significant portion of this growing market.
• Differentiation by Mechanism: As a Wnt pathway agonist, Restoret represents a novel mechanism of action. If clinical trials demonstrate that Restoret can meet or exceed the efficacy of current treatments with a favorable safety profile, it could be positioned as a first-line therapy or an adjunct to existing anti-VEGF therapies.
• Potential for Addressing Treatment Gaps: The clinical data suggesting Restoret’s efficacy in reducing retinal thickness and improving BCVA, combined with a well-tolerated safety profile, align well with the unmet needs for alternative treatments that could either enhance outcomes when used in combination with anti-VEGF therapies or serve as a monotherapy for patients inadequately managed on current therapies.

Conclusion

Given the early but promising efficacy and safety profile demonstrated in the AMARONE trial, Restoret could meet the significant unmet clinical need in the treatment of wet AMD and DME if these results are sustained and further improved upon in subsequent larger and longer-term trials. The potential to offer a novel therapeutic mechanism, possibly requiring fewer injections and presenting an alternative for patients who do not respond adequately to anti-VEGF therapies, and potentially all patients, underscores a substantial market opportunity.

The key to realizing this opportunity will be the continuation of rigorous clinical development to fully elucidate Restoret's efficacy, safety, and positioning relative to existing standards of care. Success in these areas could position Restoret as a significant player in the ophthalmic market, addressing both patient needs and capturing market share in the treatment of these prevalent retinal diseases.