Enrollment begins for phase 1/2 clinical study of topical presbyopia drug

EV06, a lipoic acid drop, is designed to reduce crystalline protein disulfide bonds, softening the lens and restoring accommodative amplitude.

Patient enrollment has begun for a phase 1/2 clinical trial of EV06, a topical treatment for presbyopia being developed by Encore Vision.

The compound is designed to reverse age-related changes in the crystalline lens that decrease lens elasticity and accommodative amplitude.

“It is fascinating. It’s the only clinical trial that I am aware of that is actually trying to go to the basic physiology of presbyopia, which is a reduction in the flexibility and shape-changing ability of the natural lens. This is the only project out there that I am aware of that is actually trying to treat that directly,” Richard L. Lindstrom, MD, OSN Chief Medical Editor, told Ocular Surgery News.

The FDA approved Encore Vision’s new drug application for EV06 (lipoic acid choline ester 1.5%) in October.

Phase 1/2 clinical trial

Richard L. Lindstrom

Preclinical pharmacokinetic studies showed that systemic concentrations of EV06 were negligible while pharmacologically significant levels reached the lens, according to information from Encore Vision.

Clinical safety studies showed no drug-related adverse events from EV06 administered before cataract surgery.

The 90-day phase 1/2 clinical trial will include 66 subjects between the ages of 45 years and 55 years in the early stages of presbyopia, Lindstrom said.

“You never know until you do the clinical trial, but I would think that it would be most likely to be effective in the early stages of presbyopia. It might be easier to reverse in the early stages,” Lindstrom said.

The trial will evaluate the safety and efficacy of EV06 in improving distance corrected near visual acuity. Efficacy endpoints will be mean change in distance corrected near visual acuity and the proportion of subjects who gain 10 or more letters.

Safety endpoints will be best corrected distance visual acuity, IOP, slit lamp findings, fundus findings and adverse events, according to a summary from Encore Vision.

Mechanism of action

The crystalline lens becomes stiff because of disulfide or sulfhydryl bonding between crystalline proteins within lens fiber cells. EV06 is designed to restore and maintain accommodative amplitude by reducing crystalline protein disulfide bonds. This softens the lens so it is more flexible, can change shape and has an increase optical power.

“All collagen, including collagen in the lens, cross-links over time,” Lindstrom said. “Cross-linking is what we try to cause to happen in the cornea with keratoconus. We want those [hydrogen molecules] to go away and the [sulfhydryl] to bond with the other [sulfhydryl]. That usually happens with exposure to oxidizing agents or free radicals. That’s what we’re doing with collagen cross-linking. We’re trying to create this cross-linking that makes collagen stiffer,” Lindstrom said.

Lipoic acid is intended to do the opposite of cross-linking and make the lens more flexible, he said.

“We’re trying to do the opposite of what collagen cross-linking does. We’re trying to uncross-link the collagen so that, instead of having these sulfhydryl-to-sulfhydryl bonds, we get a [hydrogen] on the end of them again, and that makes them uncross-link and it makes collagen more flexible. What we want, basically, is a more flexible collagen in the lens. We want to make the lens younger,” Lindstrom said.

Application of lipoic acid

Lipoic acid, a naturally occurring amino acid, can penetrate the cornea, aqueous and crystalline lens, Lindstrom said.

“[You] can take a human lens from a cadaver eye or even an animal lens and soak it in the solution, and it becomes more flexible and you get a greater change,” he said. “The question is, can we do that in a living human? Can we apply a topical drop of lipoic acid, have it penetrate the cornea, get into the aqueous in an adequate concentration and then soak into the natural lens and basically uncross-link the natural lens which would, arguably, ideally, make a 45-year-old back into a 40- or 35-year-old lens.”

Lindstrom suggested that the agent may also reverse the biochemical and biomechanical cascade that causes cataract.

“Arguably, if it works for the treatment of presbyopia, you might imagine that it could also potentially reverse some of the nuclear sclerotic changes that we see in cataract. But the clinical trial is actually not to treat cataract. We have reducing agents that have been used outside the U.S. in the past as drops to treat cataract based on some of the same principles,” Lindstrom said. – by Matt Hasson

Disclosure: Lindstrom reports he is a consultant for, board member of and investor in Encore Vision.

Patient enrollment has begun for a phase 1/2 clinical trial of EV06, a topical treatment for presbyopia being developed by Encore Vision.

The compound is designed to reverse age-related changes in the crystalline lens that decrease lens elasticity and accommodative amplitude.

“It is fascinating. It’s the only clinical trial that I am aware of that is actually trying to go to the basic physiology of presbyopia, which is a reduction in the flexibility and shape-changing ability of the natural lens. This is the only project out there that I am aware of that is actually trying to treat that directly,” Richard L. Lindstrom, MD, OSN Chief Medical Editor, told Ocular Surgery News.

The FDA approved Encore Vision’s new drug application for EV06 (lipoic acid choline ester 1.5%) in October.

Phase 1/2 clinical trial

Richard L. Lindstrom

Preclinical pharmacokinetic studies showed that systemic concentrations of EV06 were negligible while pharmacologically significant levels reached the lens, according to information from Encore Vision.

Clinical safety studies showed no drug-related adverse events from EV06 administered before cataract surgery.

The 90-day phase 1/2 clinical trial will include 66 subjects between the ages of 45 years and 55 years in the early stages of presbyopia, Lindstrom said.

“You never know until you do the clinical trial, but I would think that it would be most likely to be effective in the early stages of presbyopia. It might be easier to reverse in the early stages,” Lindstrom said.

The trial will evaluate the safety and efficacy of EV06 in improving distance corrected near visual acuity. Efficacy endpoints will be mean change in distance corrected near visual acuity and the proportion of subjects who gain 10 or more letters.

Safety endpoints will be best corrected distance visual acuity, IOP, slit lamp findings, fundus findings and adverse events, according to a summary from Encore Vision.

Mechanism of action

The crystalline lens becomes stiff because of disulfide or sulfhydryl bonding between crystalline proteins within lens fiber cells. EV06 is designed to restore and maintain accommodative amplitude by reducing crystalline protein disulfide bonds. This softens the lens so it is more flexible, can change shape and has an increase optical power.

“All collagen, including collagen in the lens, cross-links over time,” Lindstrom said. “Cross-linking is what we try to cause to happen in the cornea with keratoconus. We want those [hydrogen molecules] to go away and the [sulfhydryl] to bond with the other [sulfhydryl]. That usually happens with exposure to oxidizing agents or free radicals. That’s what we’re doing with collagen cross-linking. We’re trying to create this cross-linking that makes collagen stiffer,” Lindstrom said.

Lipoic acid is intended to do the opposite of cross-linking and make the lens more flexible, he said.

“We’re trying to do the opposite of what collagen cross-linking does. We’re trying to uncross-link the collagen so that, instead of having these sulfhydryl-to-sulfhydryl bonds, we get a [hydrogen] on the end of them again, and that makes them uncross-link and it makes collagen more flexible. What we want, basically, is a more flexible collagen in the lens. We want to make the lens younger,” Lindstrom said.

Application of lipoic acid

Lipoic acid, a naturally occurring amino acid, can penetrate the cornea, aqueous and crystalline lens, Lindstrom said.

“[You] can take a human lens from a cadaver eye or even an animal lens and soak it in the solution, and it becomes more flexible and you get a greater change,” he said. “The question is, can we do that in a living human? Can we apply a topical drop of lipoic acid, have it penetrate the cornea, get into the aqueous in an adequate concentration and then soak into the natural lens and basically uncross-link the natural lens which would, arguably, ideally, make a 45-year-old back into a 40- or 35-year-old lens.”

Lindstrom suggested that the agent may also reverse the biochemical and biomechanical cascade that causes cataract.

“Arguably, if it works for the treatment of presbyopia, you might imagine that it could also potentially reverse some of the nuclear sclerotic changes that we see in cataract. But the clinical trial is actually not to treat cataract. We have reducing agents that have been used outside the U.S. in the past as drops to treat cataract based on some of the same principles,” Lindstrom said. – by Matt Hasson

Disclosure: Lindstrom reports he is a consultant for, board member of and investor in Encore Vision.