Category: Blogs

Regenerating the Retina – February 2015

This article, published in the February 2015 issue of The Ophthalmologist, describes the use of stem cell-derived retinal progenitor cells (RPCs), that are being investigated for reviving/repairing/rejuvenating damaged photoreceptors to bring back sight to those who have lost it due to a retinal degenerative disease, including choroideremeia (CHM), retinitis pigmentosa (RP), Leber’s congenital amaurosis (LCA) and Stargardt’s disease (Stargardt Macular Dystrophy – SMD). It discusses the four companies that are conducting clinical research, as well as the work underway at several university and institutional laboratories.

To read the complete write up, please use the following link: https://theophthalmologist.com/issues/0215/regenerating-the-retina/

What will Ophthalmic Gene Therapy and Stem Cell treatment cost and how will we and the healthcare system pay for it? – May 2015

With the likelihood of a gene therapy and/or a stem cell treatment for retinal diseases to be approved for marketing within the next two to three years, it is time for the ophthalmic community – the suppliers, practitioners, patients and payers –  to start thinking about how much these regenerative medicine treatments are likely to cost, and how patients and the healthcare system will pay for them..

In The Economics of Gene Therapy, appearing in the May 2015 issue of The Ophthalmologist, I propose a pricing model for Regenerative Medicine in Ophthalmology, based on the population of patients to be treated, and suggest that an annuity program model, based on performance and duration of efficacy, could be used to pay for it.

Let the dialogue begin.

To read all about it, please follow this link: http://tinyurl.com/GeneTherapyCosts

What’s New in Gene Therapy for Ophthalmology – October 2015

An update of the latest clinical information in the use of gene therapy in treating several retinal diseases, including Leber’s Congenital Amaurosis (LCA); the wet form of Age-Related Macular Degeneration (wet-AMD); Choroideremia (CHM); Stargardt’s Macular Dystrophy (SMD); Retinitis Pigmentosa (RP); and Ushers Syndrome (US). Included is the proposed model of pricing for some gene therapy treatments, based on the population of patients likely to be treated.

To read the full article, published in the October issue of Retinal Physician, please follow this link: http://tinyurl.com/RetPhys-GT-Update

Optogenetics: Another Approach to Reversing Blindness – November 2015

Optogenetics is the introduction of protein-based, light-activated chemicals into still functional retinal cells in the vision chain, that upon activation, send electrical signals along the optic nerve to the brain, providing rudimentary vision, that was lost with the death or damage of the photoreceptors.

This report, The Optogenetics Option, describes the efforts of four companies and ten universities, using either gene therapy, or other means, to deliver light-activatable proteins or chemicals (photoswitches) to still functioning cells within the retina (ganglion and/or bipolar cells) or, in some cases, the use of light activatable implants, that will deliver light signals to the brain to provide some rudimentary vision when the photoreceptors, that normally provide that function, cannot.

To read the article, published in the November issue of The Ophthalmologist, please follow this link: http://tinyurl.com/OptogeneticsOption

Additional Marketing Approvals for Iluvien; A New Ophthalmic Application; and An Interesting Human Interest Story – January 7, 2015

Since I last wrote about Iluvien, Alimera Sciences and pSivida have announced additional marketing approvals for its use in treating chronic DME. The product is now approved for use in fourteen countries, including the U.S. In addition, pSivida is about to begin a Phase III study of its Medidur device for the treatment of uveitis, which should lead to a fast-track to approval.

But the real reason for this update was the recently published story about how an eye doctor reached out to Paul Ashton, CEO of pSivida, to package an old HIV anti-viral, ganciclovir, in his drug delivery system, to save the sight of a person undergoing chemotherapy for leukemia, who also needed a bone marrow transplant. The chemo and radiation treatment for the bone marrow transplant weakened his immune system, preventing control of his cytomegalovirus condition that began attacking his retina. Instead of painful weekly anti-viral injections, the doctor sought to use Paul’s drug delivery system to systemically treat the virus in the eye.

To read the whole story and the results, and for the latest information about Iluvien, please follow this link: http://tinyurl.com/IluvienUpdate9

Oraya Therapeutics Now Operating at Nine European Centers and Strikes Partnership Deal with Carl Zeiss Meditec – January 15, 2015

With the presentation of the three-year safety results of the INTREPID study (at EURETINA), to evaluate the safety and efficacy of the Oraya Iray Therapy in conjunction with as-needed anti-VEGF injections for wet AMD, and the recent collaboration agreement with Carl Zeiss Meditec, Oraya Therapeutics is well on its way in implementing its growth strategy in commercializing Oraya Therapy in Europe and, some day, in the U.S.

The company now has nine centers providing therapeutic treatment in Europe; four centers in the UK, one in Switzerland, and four in Germany.

To read more about this combination treatment to reduce the number of anti-VEGF treatments needed to control wet AMD, and the collaboration agreement with Carl Zeiss Meditec, please see: http://tinyurl.com/OrayaUpdate3

Avalanche and Univ. Of Washington Collaborate to Defeat Color Blindness – March 27, 2015

Avalanche Biotechnologies in Menlo Park and the University of Washington in Seattle announced a licensing agreement to develop the first gene therapy treatment for treating color blindness. The deal brings together a gene therapy technique developed by Avalanche with the expertise of vision researchers at the University of Washington.

In addition, Avalanche will incorporate research licensed from UCal Berkeley to deliver the gene therapy treatment non-surgically via an  injection into the vitreous, rather than into the retina.

To read more, please follow this link: http://tinyurl.com/AvalancheBio2

A New Laser Procedure to Turn Brown Eyes Blue – April 8, 2015

As Crystal Gayle sang in her smash hit, `Don’t It Make My Brown Eyes Blue’, now (soon) you will be able to permanently change your brown eyes to blue. A California company has come up with a laser procedure that will safely accomplish this in about 30 seconds per eye. Human clinical testing is underway and the company, Strōma Medical, hopes to have the procedure on the market (outside of the U.S. first) in less than two years, once the clinical trials are completed.

To read the rest of the story, please follow this link: http://tinyurl.com/brown-to-blue

Laser Vitreolysis Update: Ellex launches a “doctor finder” to find docs using its laser to treat floaters. – June 30, 2015

My article about the use of lasers to treat floaters, written five year ago, remains the most widely read piece on my blog. I frequently am asked if I have updated the list of doctors who now use lasers to treat floaters – in addition to the three I profiled in my U.S. writeup (Using Lasers to Treat Vitreous Floaters: Laser Vitreolysis) and the six doctors in the UK/Europe piece (Using Lasers to Treat Vitreous Floaters: Laser Vitreolysis in the UK and Europe).

I took notice when Ellex Medical announced a new YAG laser specifically for treating floaters in the fall of 2012, and about six months ago, I decided to request a list of doctors who have obtained the laser, and were now treating patients’ floaters. Better than a list, Ellex decided, to respond to my request, by building an app to locate doctors using their laser and put it on their website. That app is now active and is applicable to doctors worldwide using the new Ultra Q Reflex YAG laser to treat floaters. As of June 30th, there are 58 physicians listed worldwide using this laser.

To read more about the laser and use the app, see my update: http://tinyurl.com/vitreolysis-Update

First Spark Therapeutic Phase III Clinical Trial Results and Phase I Longevity Data – Insight into the trial results – October 14, 2015

Some insight into the Spark Therapeutics Phase III clinical trial results and longevity data. In this report, the company’s principal investigator, Dr. Stephen Russell presented highlights of the initial findings in this important Phase III clinical trial, that could lead to the first gene therapy approval in the United States.

Basically, it was found that the injection of SPK-RPR65 did lead to increased functional vision for the treated patients, compared to the control subjects – and the effect appears to last for over three years, based on the original patients treated in the Phase I study.

Is this the “forever fix”, or a step along the way? To read the full story, please follow this link:  http://tinyurl.com/GeneTherapyUpdate22

Oraya Therapeutics Receives Guidance for Adjunctive Use in Germany for wet AMD – October 20, 2015

Three German ophthalmological groups provided guidance for German ophthalmologists to better identify those patients with wet AMD that might benefit from the use of the Iray Stereotactic Radiotherapy System as an adjuctive treatment to the use of anti-VEGFs in the treatment of neovascular macular degeneration, based on studies conducted by the company to date.

To read the full story, please follow this link: http://tinyurl.com/OrayaUpdate4

The German Ophthalmological Society, the Retina Society and the Professional Association of German Ophthalmologists (DOG) have issued a joint opinion on the adjunctive use of radiotherapy with Oraya Therapeutics’ IRay Stereotactic Radiotherapy System for wet AMD. Their opinion makes it possible for ophthalmologists throughout Germany to identify patients that can benefit from Oraya Therapy in conjunction with anti-VEGF treatment.

Oraya Therapy is currently commercially available at eleven sites in Europe, with more than 550 patients treated to date with Oraya Therapy in three European countries – Germany, Switzerland and the United Kingdom.

According to the opinion, which takes the study data published to date into account, adjunctive stereotactic radiotherapy of neovascular AMD with the IRay system can be considered on an individual basis. Some of the parameters that ophthalmologists should consider include:

●    If symptoms of choroidal neovascularization (CNV) activity such as intra-retinal fluid of bleeding are present, corresponding to a recommendation of VEGF inhibitors;

●    If the ongoing anti-VEGF therapy has taken place over a period of at least six months, thus ruling out undertreatment; and,

●    If despite intensive injection therapy, no charge in the activity state of the CNV is achieved and there is no reasonable expectation of a decrease of the required high frequency of retreatment for the future.

“The joint opinion now provides guidance for ophthalmologists throughout Germany to identify those patients who can benefit from Oraya Therapy for wet AMD. There is a large patient population that does not respond well to anti-VEGF monotherapy, and our aim is to offer these patients in Germany an additional option to maintain their vision and also decrease the burden of frequent injections,” said Oraya Therapeutics CEO Jim Taylor. “We are well positioned with our IRay system at major university eye clinics in Germany, and will continue to expand our presence to make the therapy available to the patients who qualify and elect to pursue this alternative.”

The full opinion, titled “Stellungnahme von DOG, RG und BVA zur Strahlentherapie bei neovaskulärer altersabhängiger Makuladegeneration” is accessible within the German Ophthalmological Society website at:  http://www.dog.org/wp-content/uploads/2015/10/Stellungnahme-RG-DOG-BVA-zur-Strahlentherapie-bei-neovaskul%C3%A4rer-altersabh%C3%A4ngiger-Makuladegeneration.pdf.

The IRay Radiotherapy system is a CE marked medical device. In the U.S., the IRay system is an investigational device and is not yet available for sale.

Principal Investigator Stephen R. Russell, MD, of the Stephen A. Wynn Institute for Vision Research at the University of Iowa, presented Phase III data highlighting the rate, breadth and magnitude of changes following administration of SPK-RPE65 to patients with Leber’s Congenital Amaurosis (LCA), at the Retina Society Meeting held in Paris on October 10th.

In addition, Dr. Russell presented data on the three-year durability of improvements in the same measures of functional vision and light sensitivity in a cohort of subjects from the earlier Phase I trial.

This presentation built on top-line results of a randomized controlled multi-center Phase III trial previously announced by Spark on October 5, which demonstrated a highly statistically significant improvement in the intervention group compared to the control group in the primary endpoint and two of three secondary endpoints.

Data presented highlighted a mean improvement in the functional vision of intervention subjects (n=20) of 1.9 specified lux levels, compared with an improvement of 0.2 specified lux levels in control subjects (n=9) as measured by the change in bilateral mobility testing (MT) between baseline and one year in the modified intent-to-treat (mITT) population. The mITT population (n=29) includes all subjects that received SPK-RPR65, and only those who continued beyond the baseline study visit. Two subjects in the intent-to-treat (ITT) population (n=31) that were randomized but never received SPK-RPE65 are excluded from this efficacy analysis population. Thirteen of the 20 subjects receiving SPK-RPE65 were able to pass the MT at one lux at year one, demonstrating maximum improvement measurable on the MT score. None of the nine control subjects followed was able to pass MT at one lux at year one.

In a corresponding finding in the first secondary efficacy endpoint, full-field light sensitivity threshold testing (FST*) for white light, intervention subjects demonstrated a highly statistically significant mean improvement of -2.06 log10 (candela second/m2) compared with decline of 0.04 log10 (candela second/m2) among control subjects (all analyses in mITT population).

Dr. Russell presented additional top-line analyses from the pivotal Phase III trial showing the rapid and sustained impact of SPK-RPE65 throughout the entire one-year study period. Significant differences emerged in both MT and FST by the first study visit, at 30 days. These effects were reproduced consistently at each subsequent study visit (at days 90, 180 and one year).

Dr. Russell said, “It’s exciting to see a consistency of improvement between the functional vision and visual function. The parallel effect seen in the prompt response in both the primary and first secondary endpoints highlights a critically important finding from the trial: that functional improvements measured through the mobility test change score correspond closely with the physiologic impact seen through FST.”

In addition, Dr. Russell presented data on the durability of effect after three years as measured by MT and FST in a cohort of subjects that participated in the Phase 1 open-label study, and would likely have met the eligibility criteria for the Phase 3 trial. All of these subjects continue to experience a durable improvement over three years from the time of administration to the contralateral, or second eye, with observation ongoing. These subjects received the same dose and volume of SPK-RPE65 that was used in the pivotal Phase 3 trial. The figures below reflect data from all subjects available for follow-up at each time point reported. Spark and the clinical investigators continue to follow study participants to evaluate the durability of response, and will provide further updates in the future through a series of peer-reviewed presentations and publications.

“We are pleased to provide these additional informative data, the totality of which highlight the rapid, sustained and durable effect associated with SPK-RPE65 across multiple functional and physiological parameters, at time points ranging from 30 days to three years,” said Jeffrey D. Marrazzo, co-founder and chief executive officer of Spark. “We will continue to analyze the data from our groundbreaking pivotal Phase 3 trial in order to further elucidate the potential positive, meaningful impact that SPK-RPE65 can have on the lives of patients with RPE65-mediated blinding conditions.”

The pivotal Phase 3 trial of SPK-RPE65 is the first successful randomized, controlled Phase 3 trial ever completed in gene therapy for a genetic disease. The multicenter trial randomized 31 subjects with confirmed RPE65 (LCA) gene mutations. The ITT population included 21 subjects in the intervention group and 10 in the control group.

For the primary endpoint, subjects were evaluated at multiple time points over the course of one year for their performance in navigating a mobility course under a variety of specified light levels ranging from one lux (equivalent to a moonless summer night) to 400 lux (a brightly lit office) using the bilateral testing condition. Each attempt was recorded, and the videos were sent to independent, centralized, masked graders to assign a pass/fail score based on speed and accuracy with which the subjects navigated the course.

In addition to the primary endpoint, the statistical analysis plan included three secondary endpoints tested statistically in the following hierarchical order:

●    FST (white light), which reflects underlying physiological function by measuring light sensitivity of the entire visual field.

    

●    Change in MT score for the assigned first eye, which compares the MT performance between baseline and year one for the first eye injected for the intervention group and, for the control group during the control year, the first eye injected after they crossed over.

●    Visual acuity (VA) testing, which measures changes in central vision by assessing the ability of the subject to read a standard eye chart.

A summary of top-line efficacy results follows:

Primary outcome (ITT)    

MT change score, bilateral      p = 0.001

Secondary outcomes (ITT)    

FST, averaged over both eyes               p < 0.001

MT change score, first injected eye      p = 0.001

VA, averaged over both eyes                p = 0.17

In a story about the trial results published by Bloomberg Business News, the reporters commented, “A gene therapy maker showed this week it could make blind children and adults see. But the big question left is how long the effect will last.”

“Much depends on the answer, including how much the company can charge for the drug — a price tag some say could be more than $1 million a patient.”

The company has shown the effect has lasted for as long as three years without degradation of vision in some patients, providing back functional vision to those nearly blind children treated in the initial clinical trial.

According to Dr. Russell, the principal investigator, “Investors will look at the data and are going to go, `Wow this is the best data we’ve seen, not just in the eye, but on gene therapy, period’ and they’re right,”

Yet he cautioned that more information is needed before the drug can be considered a cure. While it produces a missing enzyme needed to sense light, it can’t restore light-sensing cells that have already died off due to this progressive disease. In the initial study results, released on October 5th, one standard measure of vision, visual acuity, didn’t improve by a statistically significant amount. (But, functional vision did!)

Spark also hasn’t finalized and published data on individual patients, and it’s possible that some responded better than others. “Age in particular may be a factor in how much a patient can improve,” said Dr. Russell. The company said in its statement that no serious adverse events have been seen so far in the trial.

So, the question remains, is this the “forever fix”, as author Riki Lewis has written in her book on gene therapy, or something less? Time will tell. But this is certainly an important step forward for the treatment of an inherited retinal disease.

1.  What’s New in Gene Therapy for Ophthalmology?, Irv Arons, Retinal Physician, October 2015.

2. Spark Therapeutics Announces Presentation of Additional Phase 3 and Durability Data on SPK-RPE65 at The Retina Society 48th Annual Scientific Meeting, Company News Release, October 10, 2015.

3. Presentation: Phase 3 Trial of AAV2-hRPE65v2 (SPK-RPE65) to Treat RPE65-Mediated Inherited Retinal Dystrophies (IRDs): Top-line Safety and Efficacy Results,

Stephen R. Russell MD, Retina Society Meeting, Paris, Stephen R. Russell MD, October 10, 2015.

4. Spark Therapeutics Announces Positive Top-line Results from Pivotal Phase 3 Trial of SPK-RPE65 for Genetic Blinding Conditions, Company News Release, October 5, 2015.

5. ‘Holy Grail’ Seen as Gene Drug for Blind Produces Lasting Effect, Caroline Chen & Robert Langreth, Bloomberg Business News, October 10, 2015.

Since my first article on the use of a YAG laser to treat floaters (Using Lasers to Treat Vitreous Floaters: Laser Vitreolysis) appeared in this space in August 2010, it has become the most popular/read write-up that I have posted. About 10% of all visitors to my blog come to read that article – and I’ve had over 215,000 unique visitors. One of the most frequent questions I get asked is, is there anyone close to where I live that does the procedure? Since I haven’t kept track of who besides the three doctors I featured in that first write-up are now doing the procedure, and since Ellex Medical (Ellex) now produces and markets a specialized laser (the Ultra Q Reflex) specifically to treat floaters, I decided it was time for this update.

As described by Ellex, upon release of their new laser in the Fall of 2012, here are its features:

“Featuring Ellex’s proprietary Reflex light delivery system, our ophthalmologist customers can  use the Ultra Q Reflex YAG laser to treat floaters in a medically-reimbursable procedure, known as YAG laser vitreolysis,” according to Ellex CEO Tom Spurling.

“The Ultra Q Reflex is optimized for performing YAG laser treatments both in the anterior segment and posterior segment – making it ideal for the all conventional YAG laser treatments such as capsulotomy and iridotomy, as well as YAG laser vitreolysis for the treatment of floaters,” added Mr. Spurling.

I contacted Ellex Laser management and requested a list of the U.S. doctors who have purchased this laser and who now use it to treat their patient’s vitreous strands/floaters. The company, in response to my request,  has set up an application on its website, called “Find a Physician”.

By entering your location, a map will appear which will locate doctors near you that have access to this specialized laser and use it to treat vitreous floaters by performing laser vitreolysis. The link to the app is: http://www.floater-vitreolysis.com/find-a-physician/

PS: The app works worldwide!

(As of the date I checked – June 30th – there were 58 physicians listed worldwide.)

Good luck to all.

Using Lasers to Treat Vitreous Floaters: Laser Vitreolysis, August 4, 2010

Ellex Launches Multi-Modality YAG Laser at the 2012 American Academy of Ophthalmology, November 7, 2012