Topical treatment for neovascular AMD within sight


A novel vascular endothelial growth factor receptor 2 (VEGF-R2) topical eye drop, PAN-90806 (PanOptica, Inc.), may revolutionize the treatment of neovascular age-related macular degeneration by making intravitreal injections of anti-VEGF drugs a thing of the past for certain patients and eliminating the risk associated with the intravitreal injections.

Dr. CousinsDurham, NC­-A novel vascular endothelial growth factor receptor 2 (VEGF-R2) topical eye drop may revolutionize the treatment of neovascular age-related macular degeneration (AMD) by making intravitreal injections a thing of the past for certain patients.  

A major advantage for this topical therapy (PAN-90806, PanOptica Inc.) is that the risks associated with intravitreal anti-VEGF injections to treat AMD would be eliminated. The drug was found to be efficacious for patients with wet AMD who presented with milder lesions, characterized by thinner subfield thickness and small area.

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This molecule, according to Scott Cousins, MD, is a selective inhibitor of VEGF-R2 (50% inhibitory concentration, 1.27 nm). Dr. Cousins is the Robert Machemer Professor of Ophthalmology and Immunology, vice chairman for research, and director of the Duke Center for Macular Diseases, Duke Eye Center, Durham, NC.

In a phase I/II dose-ranging trial for neovascular AMD, Dr. Cousins and colleagues sought to assess the safety and tolerability of the drug, establish a topical maximal tolerated dose, and look for signals of biologic activity.

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In the stage 1 monotherapy study phase, 40 patients were treated with 1 of 5 doses of PAN-90806, ranging from 1 to 4 mg/ml once to twice daily for 8 weeks. In the stage 2 maintenance study phase, in which 10 patients participated, 1 intravitreal injection of ranibizumab (Lucentis, Genentech Inc.) was administered, followed by 1 mg/mL of PAN-90806 once daily for 12 weeks.

Courtesy of Scott Cousins, MD

The administration of rescue ranibizumab injections was based on worsening of the visual acuity by 10 letters and findings of increased thickening on optical coherence tomography (OCT), Dr. Cousins explained.

A responder to PAN-90806 was defined as a patient who:

• did not need rescue therapy with ranibizumab;

• was able to continue the topical therapy without signs of toxicity;

• showed evidence of a clinical response on imaging that was reviewed by retina specialists masked to the treatment doses and agreement of at least 2 experts that there was a qualitative, clinically relevant, response regarding intra- and subretinal fluid, blood, lesion, size, and fluorescein leakage, and evidence of a Wisconsin Reading Center quantified anatomic response on OCT and fluorescein angiography.


Study findings

Dr. Cousins reported that no treatment-related systemic adverse events developed.

A dose-dependent keratopathy developed in association with the 3 highest doses of PAN-90806. However, although the cases were reversible, this prevented the full enrollment of these cohorts.

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The keratopathy cases were characterized by an irregular surface, fluorescein staining, occasional edema, and pain. Resolution was seen in a few days after the drop was discontinued.

Courtesy of Scott Cousins, MD

The keratopathy was thought to have resulted from high corneal drug levels with off-target inhibition of the corneal epidermal growth factor receptor (EGFR), which is crucial for corneal epithelial renewal and repair.

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“This problem was solved with development of a new suspension formulation,” Dr. Cousins added. 

The investigator saw better tolerability with the 2 lowest doses, 1 and 2 mg/ml instilled once daily.  The results from these 2 cohorts were used to analyze the drug efficacy. The lowest dose was found to have no drug-related, corneal adverse events.  

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In the phase I/II study of the 1 and 2 mg/ml doses administered once daily, 10 of 20 eyes required rescue therapy with ranibizumab. One of 20 eyes discontinued therapy because of toxicity. Nine of 20 eyes were considered responders in the stage 1 segment, according to Dr. Cousins.

Courtesy of Scott Cousins, MD

Patients who received the 1 mg/ml dose had a 12-letter increase in vision. Those who received the 2 mg/ml dose lost 1 letter of vision.

At the 8-week time point, both the central subfield thickness and the center point thickness decreased with the 1 and 2 mg/ml doses, but substantially more with the higher dose.

Both the total lesion size and the area of fluorescein leakage decreased with the 2 lowest doses. Regarding the lesion size, more of an effect was seen with the 2 mg/ml dose at 8 weeks. Regarding fluorescein leakage, a similar effect was seen at 8 weeks with the two doses.


Responders vs. non-responders

The baseline differences between the patients who benefitted from the PAN-90806 drops provided important clues to candidates for the treatment. “Responders had thinner central subfields on OCT, smaller lesions, and a smaller area of fluorescein leakage,” Dr. Cousins reported.

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He recounted a representative case of a responder with an occult lesion with subretinal fluid, moderate thickening, and vision loss at baseline. On day 1, the central subfield thickness was 286 µm and the visual acuity 66 letters on ETDRS vision testing. At week 8, the thickness had decreased to 213 µm.

Ultimately, 8 of 10 subjects in the stage 2 maintenance phase of the study completed 12 weeks without the need for rescue ranibizumab injections. Five of the 10 (50%) were considered responders (according to the expert reviewers with same clinical criteria as in stage 1).

The new formulation

The transscleral route is how topical drugs reach the choroid, Dr. Cousins noted.

The key issue for improving the formulation was minimizing corneal exposure to the drug. When the new formulation was analyzed in a primate study, the corneal concentrations were below the level of toxicity in all doses tested. The new formulation showed almost five-fold higher levels in the choroid, compared with the formulation used in this study, Dr. Cousins explained.

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“These results strongly suggest that it is very possible to develop a topical inhibitor of VEGF,” Dr. Cousins concluded. “If this drug ultimately gets approved, it will revolutionize how we treat patients with neovascular AMD, diabetic retinopathy, and other retinal conditions driven by VEGF.”

A phase I/II trial of the next generation of the formulation is set to begin in the first and second quarters of 2017.



Scott Cousins, MD

Dr. Cousins is a consultant to PanOptica Inc.



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