What's Coming Next in PC-IOLs?

Interesting designs abound, but approvals are not imminent.

It's been more than six years since the first generation of widely adopted presbyopia-correcting IOLs earned FDA approval, accompanied by the landmark breakthrough of patient-shared billing. That group of PC-IOLs included two multifocal lenses, Alcon's Restor and AMO's Rezoom, and one accommodative, the Crystalens (developed by eyeonics and later purchased by Bausch + Lomb). The so-called “premium” category also came to encompass the Staar and Alcon Acrysof toric IOLs.

The Restor and the Crystalens have both been significantly improved in recent years while AMO has a newer first-line premium lens in the much-praised Tecnis multifocal. These advancements in lens technology, significant as they may be, still leave the overall PC-IOL landscape much as it was back in 2005.

The questions remain. Where are the new players? Where are the new premium IOLs? And how much longer will it be until increasingly impatient surgeons see some new PC-IOLs available in the US marketplace?

Praise for the Synchrony

Several of the more promising presbyopia-correcting IOLs that are still in the investigational stage have been put in the “next big thing” category for many years, yet approvals have been slow in coming.

For years, article after article in ophthalmology publications, including this one, have pointed to the dual-optic Synchrony as one of the lenses that will make a significant impact upon the PC-IOL marketplace when approved. The Synchrony, which was developed by Visiogen and purchased by AMO in 2009, provides accommodation through the tensing and relaxation of the zonules through ciliary muscle movement.

Though the Synchrony is approved and now used routinely in Europe, the FDA is still evaluating Synchrony's revolutionary dual-optic design and the precise technique required to implant the lens. AMO says the company continues to address the FDA's questions.

John Hovanesian, MD, FACS, of Laguna Hills, Calif., an investigator for the Synchrony, has implanted approximately 40 of the lenses thus far and says he is “very pleased” with the results he has achieved.

“With the dual-optic design, Synchrony has the potential to provide a high level of accommodation,” says Dr. Hovanesian, noting that the lens's revolutionary design does put some additional demands on the surgeon, including the requirement for a perfectly centered, well-defined capsulorhexis.

The highly praised Synchrony IOL is still awaiting FDA approval.

David F. Chang, MD, of Los Altos, Calif., who was the medical monitor for the US trial for Synchrony, notes that the IOL is delivered through a pre-loaded injector, which allows implantation through a clear corneal incision. He agrees with Dr. Hovanesian on the need for a well-centered capsulorhexis that must completely overlap the forward-moving anterior optic to restrain it from prolapsing into the anterior chamber.

“This is the first IOL design that keeps the capsular bag expanded, and I have been impressed by the lack of progressive capsular fibrosis that we would have typically seen with a plate haptic silicone IOL,” adds Dr. Chang.

“Once you have mastered the capsulorhexis, the safety record is quite good,” Dr. Hovanesian notes, “I am not hearing about any problems with this lens.”

Asked why the Synchrony approval process has gone on for so long in the United States, Dr. Hovanesian says “the FDA has been slow to approve surgical technologies in recent years.” He surmises that “the FDA is poring over the trial data in great detail” but does not envision the need for another Synchrony trial. “I see no indication of another trial,” he says.

Dr. Hovanesian says that the emergence of femto-phaco should work to the advantage of future Synchrony adoption.

“The Synchrony design and strict implantation requirements are very complementary with a femto-phaco procedure,” he says. “The possibilities are very exciting.”

The Calhoun LAL: A Total Departure

Another investigational PC-IOL whose potential has been discussed for years is the Calhoun Light-Adjustable Lens (LAL) from Calhoun Vision. The company was founded in 1999 by two Californians, ophthalmologist Daniel Schwertz, MD, and chemistry professor Robert Grubbs, PhD, winner of the 2005 Nobel prize in Chemistry.

Their revolutionary idea was to quickly and easily eliminate residual refractive error following cataract surgery without removing the IOL from the eye. Though the Calhoun lens is unremarkable and traditional in its three-piece design, its secret is in the photosensitive materials (called macromers) used to construct the lens. The shape and power of the lens can be changed non-invasively by bringing the patient back two to three weeks after surgery and focusing a near-ultraviolet light on the macromers in a two-minute procedure. The procedure can be repeated later if further adjustment is needed.

Calhoun LAL is already commercially available in the European Union and a US clinical trial for the lens began in 2009. Several recent ARVO presentations from Spanish researchers have confirmed the effectiveness of Calhoun Vision's light-adjustment technology, especially in patients who have had previous refractive surgery.

The Calhoun LAL is unique in that it can be adjusted by near-ultraviolet light after it is in the eye.

In one such ARVO presentation, researchers from Murcia, Spain, concluded:

“We have successfully used the LAL to optimize the refractive and aberration outcomes in post-LASIK cataract patients. This type of adjustable technology is especially well suited for these type of patients who may present large refractive surprises and have large corneal aberrations induced by the previous LASIK procedures.”

The developers of the Calhoun LAL believe that their light-adjustable technology has barely scratched the surface of its potential. They envision a future role for LAL in correcting astigmatism and higher-order aberrations and have already had some success in correcting astigmatism.

The Tetraflex: A Long History

According to its developer Lenstec, the single-piece Tetraflex accommodative IOL has a long history of more than 50,000 patients implanted with the lens worldwide. Though the Tetraflex has not yet been approved for commercial use in the United States, US clinical trials were completed more than a year ago and the company is awaiting word from the FDA.

In addition to the original Tetraflex lens, which comes with its own injector system and that can be implanted with as small as a 3-mm incision, the company has developed an aspheric version called the Tetraflex HD. The Tetraflex HD is already approved in Europe and Lenstec says it represents an improvement over the original Tetraflex. Once FDA approval is received for the original Tetraflex, the company plans to transition its US marketing effort to the Tetraflex HD.

Lenstec describes the hydrophilic acrylic Tetraflex as having a unique design with a five-degree angulation.

“This represents a five-degree start to near-vision adaptation of the implant with eye physiology and movement inside the eye,” says the company. “The Tetraflex is designed with a five-degree start to flex and adapt with the natural physiologic movements inside the eye when a patient focuses near, intermediate and far. The lens is designed to work along with the natural forces inside the patients' eye. The haptics are designed in a “ribbon” type flex, not a hinge. This is the key to its performance. The Tetraflex will not hinge forward or backwards and stick in an undesired position.”

Several top US cataract surgeons, asked for their opinion of the Tetraflex, described it as mildly accommodative. Perhaps because it uses a more traditional design, it has not garnered the attention that some other investigational IOLs have generated.

The FluidVision: Early Results Promising

The FluidVision IOL, a fluid-driven accommodative lens, is being developed by PowerVision of Belmont, Calif., and has already completed a successful six-patient phase 2 trial under the supervision of the highly respected cataract surgeon Louis “Skip” Nichamin of Brookville, Pa.

Advantages of the FluidVision IOL are a wide range of natural accommodation and ease of implantation.

The excitement about the FluidVision primarily stems from its potential to offer greater than 5 D of accommodative power through the internal movement of the lens. In the small trial, Dr. Nichamin reported that all patients achieved excellent visual acuity and all were within 1 D of emmetropia. The average accommodative power for the six patients was 5.6 D.

“The FluidVision lens mimics the natural accommodative process of our crystalline lens with a shape change and forward movement,” said Dr. Nichamin in reporting his phase 2 results.

The key to the wide range of accommodation provided by the FluidVision is that the natural muscle movement of the eye moves the silicone fluid in the IOL to change the shape and thickness of the lens. Dr. Nichamin notes that the silicone fluid is similar to the fluid used in retinal tamponades and thus has been proven to be highly biocompatible with the eye. The outer portion of the IOL that encases the fluid is made from a proprietary hydrophobic acrylic that is matched to the same refractive index as the fluid within.

In recent months, PowerVision has been working to develop an injector delivery system that will allow the IOL to be implanted through a traditional small incision.

“There definitely have been continued advances with the delivery system and the lens itself,” says Dr. Nichamin. “We are making incremental improvements. Replicating the accommodative movement of the natural lens in an IOL is the holy grail. It is a major task.”

“We have been flying below the radar for a while,” adds Matthew Frinzi, co-founder and chief business officer of PowerVision. “However, that is changing. We have venture capital financing totaling $53 million (recently adding medical device leader Medtronic as a backer) and are preparing to soon initiate a European trial to obtain EU approval.”

Co-founder and CEO Barry Cheskin has already shepherded several medical device startups to commercial success. He believes that the wide range of natural accommodative power provided by the FluidVision IOL, coupled with a basic in-the-bag implantation procedure that's familiar to surgeons, will make FluidVision a winner with either traditional surgery or femto-phaco.

“We know there will be competition, but cataract surgery is a huge and growing market,” he asserts. “We are very confident concerning the advantages of our lens.”

NuLens: Placement in the Ciliary Sulcus

NuLens Ltd. is an Israeli company that was formed in 2002 with the purpose of researching and developing innovative ophthalmic technologies. The company has received funding from venture capital investors, including a 35% stake owned by Tel Aviv-based Elron, which has backed numerous successful technology and medical device companies since 1962.

The most dramatic innovation to come from this startup is the NuLens accommodative IOL, a lens filled with silicon gel that uses the eye's own muscles to change the shape of the lens, providing a wide range of accommodation.

In the use of a fluid or gel to change the shape of the lens to provide accommodation, the NuLens is similar to the FluidVision IOL. However, there are major differences between the two lenses.

Jay Pepose, MD, PhD, of St. Louis, says the NuLens' design is based upon the mechanism of accommodation used by diving fowl.

“These fowl need to find their target while in the air and continue to track it when they dive into the water, which requires extraordinary accommodating ability,” explains Dr. Pepose. “Their crystalline lens in pushed through a rigid, muscular iris, creating a tremendous change in shape. Similarly, the NuLens is placed in the ciliary sulcus over a collapsed capsular bag, which serves as a diaphragm.”

The forces derived from the ciliary muscle are translated to the capsular diaphragm onto a piston, which pushes a gel-like deformable lens through a rigid hole, thereby creating a bulge in the lens. Dr. Pepose says the resulting change in shape of the anterior IOL is profound and results in up to 10 D change in dioptric power.

The mechanism of the current IOL design works by “reverse accommodation,” Dr. Pepose notes. “Anecdotally, in those implanted with the lens to date, there appears to be rapid adaptation and enough accommodative reserve for the patient not to fatigue. The IOL design obviates the effect of individual variations in capsular bag shape, diameter and fibrosis, which have been challenging to current accommodating in-the-bag lens designs.”

The NuLens performed well in terms of increasing visual acuity in a 10-patient clinical trial conducted by Jorge Alio, MD, of Spain. The patients in this preliminary trial had both cataract and atrophic macular degeneration. However Dr. Pepose did note several potential issues with the early lens design that were found in the initial study are being addressed in newer iterations of the NuLens. These include “a high rate of capsular opacification, a 9-mm wound incision with induction of astigmatism and a high initial loss of corneal endothelium.

Dr. Pepose explained that “the latest modifications of the initial NuLens design allow a much smaller wound incision, as well as a posterior square edge and acrylic base lens to press against the collapsed lens capsule to minimize PCO formation.”

The company's initial goal is EU approval, with the aim of US approval by 2014.

PC-IOLs With Success in Europe

Three presbyopic lenses that have had success internationally are the mildly accommodative, single-piece foldable hydrophilic acrylic 1CU from Human Optics of Erlangen, Germany and the AcriLisa multifocal and AcriLisa Toric acrylic IOLs from Carl Zeiss Meditec. Both AcriLisa IOLs can be implanted with very small (sub 2-mm) incisions.

It is as-yet uncertain whether Human Optics or Carl Zeiss Meditec plan to attempt to gain approval for their PC-IOLs in the United States.

The AcriLisa multifocal toric has done well in Europe. Will it be brought to the United States?

Promising Early-Stage Concepts

LentisMPlus

Though only very small European trials have been reported for the Lentis MPlus multifocal IOL being developed by the German company Oculentis, Uday Devgan, MD, of Los Angeles, finds it “an interesting idea.” He says that the Lentis MPlus “is a multifocal IOL that looks like a bifocal lens—the top for distance and the bottom for near.” The one-piece acrylic, aspheric lens is designed to allow seamless transition between the two discrete optical zones.

A German cataract surgeon reported early but promising two-month outcomes for the Lentis MPlus at this year's ESCRS meeting in Paris. She commented positively on the level of spectacle independence and good contrast sensitivity achieved by the 10 patients who were implanted with the lens, as well as the absence of halos and glare, which she attributed to the lens design.

Elenza Electronic Lens

Another new concept, this one mentioned by Dr. Pepose, is a pioneering electronic lens implant being developed by Elenza of Roanoke, Va.

“The performance of current accommodating lens implants can be influenced by variations in capsular diameter, pharmacological effects on ciliary muscle contraction, and capsular contraction and fibrosis,” notes Dr. Pepose. “The recent invention of a switchable liquid-crystal diffractive lens that can adaptively change its focusing power provides the basis for the first electro-active accommodating IOL.”

Dr. Pepose says the operation of the lens is based on electrical control of the refractive index of a nematic liquid crystal sandwiched between a circular array of photolithographically defined transparent electrodes. The components of this hydrophobic IOL with hermetically sealed circuitry include a monofocal static IOL with aspheric central optic for far and intermediate, additional smart electro-active diffractive liquid crystal for near micro-sensors to detect physiological triggers of accommodative effort, and on-board processors and algorithms to control the power sequence.

Lithium ion power cells with rechargeable life of at least 50 years are charged weekly by an inductive charging element. Microsensors detect differences in illumination with miosis and utilize dual application-specific integrated circuits.

Dr. Pepose says the components required for the creation of the first electro-active IOL are currently available.

“This novel IOL may offer the advantage of providing accommodation without movement,” he concludes.

Looking Ahead

Despite the numerous IOL concepts outlined in this article, some of which have extensive track records of success and safety, US approvals for PC-IOLs will most likely continue to be slow in coming. One plausible explanation is that the more revolutionary designs require extensive pre-approval study. However, other more traditional designs, also remain stuck in the pipeline. When the logjam will break is still anyone's guess, but the FDA has surprised the ophthalmic community in the past and is likely to do so again. OM