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Targeted therapy for ocular melanoma


(Figure 1) Targeted acute tumor cellular necrosis upon light activation.

(Figure 1) Targeted acute tumor cellular necrosis upon light activation.

(Figure 2) Image courtesy of Aura Biosciences, Inc.

(Figure 2) Image courtesy of Aura Biosciences, Inc.

Light-activated AU-011 has the potential to be the first targeted therapy ever developed for the primary treatment of ocular melanoma, the most common primary cancer of the eye, said Amy C. Schefler, MD, with Retina Consultants of Houston.

People diagnosed with ocular melanoma confront “an array of poor treatment options, which often result in severe vision loss, removal of the eye, and in about half of all cases, metastasis to the liver, where the disease is nearly always fatal,” according to Aura Biosciences, which developed this light-activated technology.

AU-011 is a first-in-class targeted therapy, a novel protein capsid-dye conjugate recombinantly derived from the capsid proteins of the papilloma virus; the FDA has already granted Fast Track Designation and Orphan Drug Designation, recognizing that there are no FDA-approved therapies and that the disease is serious and life-threatening, Dr. Schefler said.

The mechanism of action of AU-011 is targeted acute tumor cellular necrosis upon light activation. The capsid conjugates are delivered by intravitreal injection and selectively target the tumor cells in the choroid sparing the retina and other key ocular structures. This unique selectivity is due to the binding of the capsid conjugates to modified heparan sulfate proteoglycans (HSPGs) that are expressed on the tumor cell surface. The capsid protein is conjugated with a potent phthalocyanine photosensitizer, IRDye 700DX, that exerts its tumor cytotoxic effect through light-activation with a near-infrared 689-nm laser.

The mechanism of action has a dual selectivity. First, the capsid conjugates bind tumor cells selectively without binding other key eye structures and second, the laser beam activates the conjugated dye exclusively within the tumor generating potent cytotoxic oxygen free radical species that disrupt the tumor cell membrane, leading to targeted and acute tumor cellular necrosis, Dr. Schefler said.

In preclinical ocular tumor rabbit models, animals were treated with two weekly doses of light activated AU-011 on day 1 and day 8. The results demonstrated complete necrosis in the tumors implanted in the choroid with no damage to the adjacent retina even in tumors measuring >10mm in thickness, Dr. Schefler said.

The animal data showed a dose response effect, which means that with higher doses of the drug the tumor necrosis increased, while the retina and other healthy tissue were not affected, she said. The strength of this preclinical data enabled the Orphan Drug Designation by the FDA in 2015.

Dr. Schefler presented the interim 6-month results on AU-011.

Study design

The phase Ib/II trial is a 2-year, prospective, multicenter, open label design with single and multiple ascending dose cohorts, she said. Three patients with choroidal melanoma

Three patients with choroidal melanoma received a single intravitreal administration of the capsid conjugate at each of three subtherapeutic dose-escalating levels (20 μg, 40 μg, or 80 μg) followed by light-activation with a 689-nm laser at a fluence of 50 J/cm2 . (Dr. Schefler clarified that while this is a similar laser as used in photodynamic therapy, there was no verteporfin used).

The multiple ascending dose (MAD) phase of the study consisted of four additional cohorts of three patients each. In each cohort the number of intravitreal administrations was increased up to three weekly treatments and the number of laser activations was increased to two applications on the same day, separated by 30 minutes. The objective of the MAD was to explore the maximum tolerated dose and regimen for the phase III clinical trials.

The primary trial objective was safety, with secondary outcomes including efficacy and immunogenicity.

Study results to date

There have been 22 patients treated to date, nine in the single ascending dose cohort, and 13 in the multiple ascending dose cohort.

“There were no treatment-related serious events or severe adverse events,” Dr. Schefler said.

Fundoscopic evaluation of patients after treatment showed that the posterior inflammation appears to start in the tumor and “is probably related to tumor necrosis.”

There was virtually no change in visual acuity (all patients followed for 6 months or longer were within one letter of baseline).

“This was regardless of where the tumor was located, including those that were right in the middle of the fovea or touching the optic nerve,” she said.

In the three single-dose cohorts, several patients had stable disease at 12 months, even though this had been considered the sub-therapeutic dose, Dr. Schefler said.

In the multiple dose cohorts, all patients maintained stable disease at follow-up and a number of patients had tumor shrinkage measured by ultrasound.

Dr. Schefler said investigators are measuring tumor growth and presuming that when there is no further growth the tumor is undergoing necrosis with no malignant potential any longer.

“Certainly, seeing tumor shrinkage and inflammation around the tumor at early time points is encouraging to confirm the biological activity of the drug, but the most important measure for efficacy is that the tumors have no further growth at longer follow up times with good vision preservation,” Dr. Schefler said.

Amy C. Schefler, MD
P: 713/524-3434
This article was adapted from Dr. Schefler’s presentation at the 2018 meeting of the American Society of Retina Specialists. Dr. Schefler is an investigator and consultant for Aura Biosciences.

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