Innovation in Retina

EDITED BY EMMETT T. CUNNINGHAM, JR, MD, PhD, MPH, AND PRAVIN U. DUGEL, MD

Bringing Functional Vision to the Blind

Second Sight Medical leads the way, but potential competitors emerge.

JERRY HELZNER, CONTRIBUTING EDITOR

While looking for a PhD project at Johns Hopkins University in the late 1990s, young physician-scientist Robert Greenberg met legendary ophthalmic innovator Eugene de Juan, MD. Dr. de Juan invited Dr. Greenberg to the operating room the next day to observe the electrical stimulation of the retina of a blind patient. Dr. de Juan and his collaborator, Mark Humayun, MD, PhD, had tested two patients in similar experiments before at the Duke Eye Center, but this was the first test at Johns Hopkins. Dr. Humayun traveled to Baltimore for the experiment.

“When Dr. de Juan placed an electrode on a blind patient’s retina and the current was turned on, the patient reported seeing a spot of light. He then did it again with a second electrode, and the patient saw two spots of light,” recalls Dr. Greenberg. “From that moment, I was hooked on the idea that, if you could attach enough electrodes, you could provide blind patients with at least some functional vision. I started to see it as essentially an engineering challenge.”

When Dr. Humayun later joined the ophthalmology faculty at Johns Hopkins University, he and Dr. Greenberg began seriously working on a retinal prosthesis concept designed to bring functional vision to blind patients afflicted with retinitis pigmentosa. Though the idea — now popularly known as a “bionic eye” — was still in its early stages, Dr. Humayun and Dr. de Juan decided that it could be better developed through a company than in an academic setting. They approached the leaders of cochlear implant companies, including philanthropist-medical innovator Alfred Mann, who had a similar technology to restore hearing.

For his part, after graduating from the MD/PhD program at Johns Hopkins, Dr. Greenberg went to work at the FDA reviewing medical devices. It was there that he also met Mr. Mann, who offered him a job working in his non-profit research foundation in early 1998.

KEY INVESTORS STEP UP

A highly positive development occurred in late 1998 when Mr. Mann and partners Sam Williams and Gunnar Bjorg became investors in the retinal prosthesis concept and asked Dr. Greenberg to run it under the name Second Sight Medical Products. The choice could not have been more auspicious. Young Dr. Greenberg was already a seasoned entrepreneur, having developed and sold a software program while in high school, and created a dormitory security system while in college that is still in use today.

“It was sort of funny,” says Dr. Greenberg. “The software company had offered me a full-time job. They had no idea I was about 15 years old.”

The Argus II implant and glasses

Dr. Greenberg had planned on becoming a practicing ophthalmologist, but accepting the opportunity to run the new company ruled that out.

“I had to think about it, but I decided to go into business, because in practice, you can help one person at a time, and here was a chance to help a much larger number of people, but in a different way.”

Mr. Williams had a very personal interest in the research, as he was himself afflicted with retinitis pigmentosa. The connection with Mr. Mann and Mr. Williams not only helped from a financial standpoint; Mr. Mann’s team was working on a number of other medical technology innovations, one of which was the cochlear implant for deafness.

“We found a lot of similarities between the cochlear implant technology and some of the issues we were working on for the retinal prosthesis,” notes Dr. Greenberg. “So our association with Alfred Mann and Sam Williams has helped Second Sight in many ways.”

A MAJOR TECHNOLOGY HURDLE

In developing their first retinal prosthesis, known as the Argus I, Second Sight had to overcome a number of technical obstacles, the most daunting being finding a way to attach the electrode array to the delicate retinal tissue without damaging or detaching the retina.

“That was probably our biggest challenge,” says Dr. Greenberg.

But there were other major hurdles as well, including making all the components of the system as small as possible, avoiding system failure after being implanted, and keeping the system sealed so that salt water from the eye did not intrude and cause a short-circuit.

Progress on the Argus I continued in the early years of the new century, including a successful six-patient clinical trial in 2002, which was conducted with Dr. Humayun at USC. Despite highly encouraging results in which patients who had been blind for decades could see large letters and even shoot a basketball into a net, because of the complexity of the surgery and the limitations of the device, it never reached the point of development where Second Sight felt it could commercialize Argus I as a product.

“Though the response from patients who received the Argus I was positive, it required an eight-hour surgical procedure with multiple surgeons and only had 16 electrodes,” says Dr. Greenberg. “We decided to take all that we had learned from the Argus I and begin with a new system called Argus II.”

ENTER THE ARGUS II

The 60-electrode Argus II benefited from a widespread effort to miniaturize all types of components, allowing the system to be more compact and efficient with a surgical procedure designed by Dr. Humayun. In 2006, a three-patient clinical trial began in Mexico, followed by a later 30-patient study in the United States and Europe. These trials enabled the Argus II to first earn the CE mark in Europe in 2011 and then FDA approval for late-stage retinitis pigmentosa in February 2013, following a 19-0 vote for approval by an FDA advisory panel. (Dr. Greenberg’s brief experience as an FDA reviewer in the 1990s helped Second Sight successfully navigate the regulatory process.) Recently, Health Canada also approved the device.

The Argus II system has three components. First, a sheet of electrodes is implanted onto the surface of the retina. A small video camera is mounted onto a pair of glasses to capture images. A transmitter and video processing unit send those images to the electrodes, which transmit them to the brain, where limited functional vision is achieved.

The current version of the Argus II depends on a connection to the optic nerve. However, Second Sight is now working on its Orion design, which connects directly to the vision center of the brain.

“In some diseases, such as glaucoma and diabetic retinopathy, the optic nerve can be too damaged to be used with the Argus II,” says Dr. Greenberg. “By bypassing the optic nerve and stimulating the visual center of the brain, we can make the system available to more patients.”

EXPANDING THE PATIENT BASE

With funds received from a recent public stock offering, Second Sight plans on studying its device for patients who are afflicted with other vision-robbing diseases, such as the dry and wet forms of AMD, glaucoma, and diabetic retinopathy.

A version of Second Sight’s implant, the Orion I, now entering animal trials, is targeted at eliminating nearly all blindness — approximately eight million patients globally. The Orion I will bypass the optic nerve and directly interface with the visual part of patients’ brains.

“One of the reasons we went public with our stock was to make more people aware of our technology,” says Dr. Greenberg. “After the FDA approval was announced, about 1,000 retinitis pigmentosa patients called us directly. It is important that RP patients know about the Argus II. Our goal now is to improve the performance of the system and expand the number of patients who can benefit from it in terms of giving them a better quality of life.”

Though Second Sight has until now had elements of a humanitarian effort, Dr. Greenberg strongly believes that the company can also be a commercial success once it reaches its break-even point of 350 implants per year. The company is also open to licensing the technology to qualified distributors around the world, with one such deal recently completed with a Turkish distributor.

PROGRESS ON REIMBURSEMENT

Though the Argus II has a six-figure price tag — nearly $145,000 for the device alone plus surgical and associated fees — Second Sight has been successful in obtaining reimbursement guidelines from parts of Medicare and private insurers.

“Reimbursement is still on a case-by-case basis in many Medicare regions, but we have had success in obtaining reimbursement, and it’s something we’re always working on.”

Internationally, progress on reimbursement is also being made, with Germany recently qualifying the Argus II for its highest level of government payment.

COMPETITION FROM STANFORD LAB

Though Second Sight Medical has the only FDA-approved retinal prosthesis and the longest history of confirmed success and patented intellectual property in this area of research, several challengers now exist. One promising approach has been developed by Daniel Palanker, PhD, and colleagues at the Hansen Experimental Physics Laboratory at Stanford University. Their technology, based on photovoltaic subretinal arrays, is now licensed to the French company Pixium Vision. The device being developed in this partnership, named Prima, is expected to be in a clinical trial in 2016.

Dr. Palanker is a highly respected innovator in the ophthalmic technology area, having contributed to the development of at least seven successfully commercialized devices, including the PEAK plasma blade, PASCAL retinal scanning laser, and femtosecond laser system for cataract surgery. He believes that the major weaknesses of other designs is that retinal electrode arrays are connected to a power supply by a cable, and they do not have enough electrodes to enable sufficient resolution for face recognition and reading. He notes that developing a high-performance retinal prosthesis presents a complex set of challenges.

“Development of a high resolution retinal prosthesis faces multiple engineering and biological challenges, such as delivery of information to thousands of pixels at video rate, placement of the electrodes in close proximity to the target cells, avoidance of fibrotic encapsulation of the implant, signal processing to compensate for the partial loss of the retinal neural network, and many others. Our system overcame these challenges using subretinally implanted photovoltaic pixels. Each pixel, similar to a solar panel, converts incoming light into electric current to stimulate the nearby neurons. Images captured by the camera are projected onto the retina from video goggles using pulsed near-infrared light. This approach allowed us to get rid of all the wired electronics, and scale the number of pixels to thousands,” says Dr. Palanker. “Since each pixel is an independent converter of light into current, pixels don’t have to be connected into one large implant. Instead, they are arranged into multiple small modules, which are inserted into the subretinal place to tile a large visual field. In addition, image processing between the camera and the goggles helps compensate for the lost image processing in the degenerated retina.”

ANOTHER CHALLENGER FROM GERMANY

A German company, Retina Implant, AG, founded in 2003, is studying a subretinal implant based on the company’s Alpha IMS Microchip technology. In 2014, the company reported 12-month results on a study of 29 patients with late-stage retinitis pigmentosa. The majority of the patients were able to see light (86%) and determine the source of the light (59%). Almost half of the patients said they could determine shapes and that the implant was helpful in their daily life, but many of these devices eventually failed — a significant challenge for implant device developers.

“Through these data, we conveyed safety of the Alpha IMS as well as evidence suggesting the device is capable of restoring impactful vision to patients with RP who were blind before implantation,” says Professor Eberhart Zrenner, cofounder of Retinal Implant and chief clinical investigator. “We look forward to submitting our results for publication in a peer-reviewed journal to further educate the ophthalmology community on the improved vision our technology enables in patients blind from RP.”

Other efforts to develop retinal prostheses are at earlier stages in both Australia and the United Kingdom. RP