Current Resources: The Use of Stem Cells and Gene Therapy in Ophthalmology

As many of you are aware, over the past couple of years, I’ve been tracking and reporting on the companies and institutions involved in research and clinical trials using both stem cells and gene therapy in ophthalmology. With the help of several industry sources, I have been able to put together the most comprehensive and up-to-date list of who is involved and what they are doing.

Because I have been updating this information almost on a daily basis, I’ve decided to no longer post the information on this Journal (Irv Arons’ Journal), as it is practically out-of-date almost as soon as I post it. Therefore, I will only offer my tables of information to those who are interested in receiving them, and put notices on the appropriate LinkedIn Forums and Twitter when there is substantial new information to report.

Here is what is currently available:

Stem Cells

Stem Cell Companies (and Institutions) Active in Ophthalmology

A list of fifteen companies and four institutions working with stem cells for ophthalmic applications. The table lists collaborators, the cell type being used, and the applications against which the cells will be applied.

Stem Cell Therapy in Ophthalmology by Applications

A list of six ophthalmic applications being tested in clinical trials. The table includes which companies/institutions are involved, the clinical trial status, and the clinical trial number for those which are currently active. (Eleven active clinical trials are listed, with live links.)

Stem Cell Therapy in Ophthalmology – Ongoing Clinical Trial Details

More detailed information about the ongoing clinical trials for the six ophthalmic applications noted above. This table includes detailed information about the clinical sites and provides the latest information about how many patients have been treated in each clinical trial.

Gene Therapy

Gene Therapy Companies/Institutions Active in Ophthalmology

The table lists nearly forty companies and institutions actively pursuing gene therapy solutions to ophthalmic diseases. The table shows the delivery viral platform, the gene type being used (where known), the application, and clinical status.

Gene Therapy in Ophthalmology by Application

This table, like the one for stem cells, lists the ophthalmic indication, the company/institutions involved, the clinical status, and the clinical trial number. (Fifteen active clinical trials are listed, with live links.)

Gene Therapy in Ophthalmology – Ongoing Clinical Trial Details

As with the Stem Cell table above, this table provides detailed information about the sixteen ongoing or completed clinical trials. It provides information about the clinical sites, the status of each clinical trial and the number of patients (or eyes) that have been treated in each trial.

Anyone interested in receiving a copy of any or all of the above tables, please contact me via email (see the link in the side bar) and let me know which ones, or all four, that you wish to obtain. The tables are in pdf format, and as mentioned, contain live links to all of the clinical trials listed.

Irv Arons

Gene Therapy in Ophthalmology Update 14: Early Positive Results in Ongoing Gene Therapy Wet AMD and Stargardt’s Disease Studies

Last week, Oxford BioMedica and its partner Sanofi announced positive results in their ongoing gene therapy clinical trials for wet AMD and Stargardt’s disease. In an interim review of their Phase I (RetinoStat) and Phase I/IIa (StarGen) trials, the Data Safetly Monitoring Board (DSMB), an independent panel of specialists in the fields of ophthalmology, virology and vectorology, gave the go ahead to proceed to a final patient cohort in the Phase I study in the case of the RetinoStat trial, and to a third patient cohort in the Phase I/IIa study of the StarGen trial.

The companies announced the following:

DSMB highlights of ongoing RetinoStat Phase I study:

● Nine patients treated to date (n=3 at each of dose levels 1, 2 and 3)

● No serious adverse events related to RetinoStat or its method of administration

● Long-term safety profile now up to 18 months post-treatment (dose level 1)

● Successful retinal transduction, as shown by substantial increase in expression and secretion of endostatin and angiostatin proteins measured in the anterior chamber of the eye following a single administration of RetinoStat. So far, expression is sustained for up to 12 months post-treatment at dose level 1 (n=3) and up to six months post-treatment at dose level 2 (n=3) (The extent of the followup to date on dose level 2. Longer term results are expected to be achieved.)

● DSMB support received to proceed to final patient cohort (n=9, confirmatory dose level)

The RetinoStat open label, dose escalation Phase I study will enrol 18 patients total with"wet" AMD and will evaluate three dose levels to assess safety and aspects of ocular physiology.

The study is led by Professor Peter Campochiaro at the Wilmer Eye Institute at Johns Hopkins, Baltimore and Oxford BioMedica has now opened a second clinical site at the Oregon Health and Science University, Portland with Dr Andy Lauer as principal investigator.

Further results from this study are expected in Q4 2012.

On the basis of pre-clinical data, it is anticipated that RetinoStat may require only a single administration which would give the product a significant advantage in the market over currently available treatments that often require frequent, repeated administration.

DSMB highlights of ongoing StarGen Phase I/IIa study:

● Eight patients treated at dose level 1 to date (n=4 severe level of disease, n=4 less severe)

● No serious adverse events related to StarGen or its method of administration

● Long-term safety profile now up to 12 months post-treatment (dose level 1)

● DSMB support received to proceed to third patient cohort (n=4, dose level 2)

The StarGen open label, dose escalation Phase I/IIa study will enrol up to 28 patients and will

evaluate three dose levels for safety, tolerability and aspects of biological activity.

In the US, the study is led by Professor David Wilson at the Oregon Health and Science University, Portland, Oregon. In France, Professor Jose-Alain Sahel leads the study at Centre Hospitalier National d'Ophtalmologie des Quinze-Vingts, Paris.

StarGen has received European and US Orphan Drug Designation which brings development, regulatory and commercial benefits.

Further results from this study are expected in Q4 2012.

As noted above for the RetinoStat treatment, on the basis of pre-clinical data, it is anticipated that a single application of StarGen to the retina could potentially either provide long-term or permanent correction. There are currently no approved treatments available for Stargardt disease.

John Dawson, Chief Executive Officer of Oxford BioMedica, said:"The continued progress of our ophthalmology portfolio, supported by another positive DSMB review, is encouraging - particularly given that early RetinoStat data demonstrate sustained therapeutic protein expression in the eye following a single administration. The favourable safety profile of our novel ocular gene therapies further supports the wider LentiVector platform safety package with over 33 patients treated to date across the ocular and Parkinson's disease programmes."

Stem Cells in Ophthalmology Update 22: A Stargardt’s Clinical Trial Patient’s Story – In Her Own Words

Back a few months ago, I got an inquiry about my tables of clinical trials published in my online Journal. I responded to the woman inquirer and found out that she was considering participating in a clinical trial. The inquirer was Maurie Hill. She has Stargardt’s disease.

We began corresponding and she told me that she was planning on going to the Wills Eye Institute in Philadelphia to be screened for the Advanced Cell Technology’s ongoing stem cell clinical trial. She was screened and accepted into the program and became the sixth patient treated, and the first of the second cohort, treated with 100,000 RPE (retinal pigment epithelial) cells derived from human embryonic stem cells (hESCs).

A little information about Maurie. She is 52, married, has a 9 year-old daughter, and lives in Vermont. She has an Associates degree in Electronics and Engineering Technology and works (and writes) for a company, Ai Squared,  involved in providing technology for the visually disabled.

Interestingly, she is one of six siblings, two others of whom also have Stargardt’s disease.

When Maurie told me that she had been accepted into the clinical trial, I suggested that she keep notes and write about her experiences. She thought that would be a good idea and here, in her own words, is the first entry in her diary.

I'm in the ACT Stem Cell Trial for Stargardt’s Disease!

by: Maurie Hill on July 31, 2012

As presented in Zoomed In, the Ai Squared Blog

Picture of Maurie after the surgery

My last article highlighted my experience at the Visions 2012 conference and the closing session's three main speakers. They spoke about some of the ongoing human clinical trials exhibiting great promise for battling retinal degenerative diseases. One of those speakers, Matthew Vincent, Director of Business Development at Advanced Cell Technology (ACT), spoke effectively about the current stem cell trials for both Stargardt disease and AMD. And even more recently, ACT announced that they treated their fourth (U.S) Stargardt patient, the first patient to receive a higher RPE cell concentration in their worst eye. I am excited to inform you that I am this patient! I was treated on July 11th at Wills Eye Institute in Philadelphia. It was an exciting experience that I'll never forget; physically joining the team within the many teams that have worked so hard to bring us to this point in medical history.

Well there's a lot to catch you up on but first I will tell you that the surgery itself, performed by Dr. Carl Regillo, went according to plan. Within a week, the doctors could no longer tell that my eye had been physically intruded upon using a common procedure called a vitrectomy. This procedure was used to remove vitreous fluid and replace it with something unusual - RPE cells derived from just one donated human embryonic stem cell (hESC). After two weeks, my vision appears to be the same as it was before surgery, which is expected at this point.

Let's back up a bit.  After seeing interviews of the first two patients in this trial on the CBS Morning News and listening to them on NPR, I wanted to know more. The Stargardt patient, who understandably wished to remain anonymous, could now read five letters on the ETDRS visual acuity chart. But what did she see in those letters beforehand? Could she see part of the letters clearly using a small remaining portion of central vision? Did the bold letters appear gray because her vision was cloudy, or did the letters appear to be completely missing from the page, as if she were looking at a white sheet of paper?

Why does that matter? Since Stargardt’s Disease is a slowly progressive disease, I wondered how many years ago was it that she could actually distinguish those letters. In other words, how many years did this procedure effectively reverse? Since these new healthy RPE cells theoretically take over the job for your current genetically deprived RPE cells in the eye, they should be "munching up" the debris that naturally flakes off your photoreceptor cells every day,.so what functional aspect of vision comes back first? Does what was lost last come back first? Though I still had nearly 20/20 vision at age 20, my ability to scan across text quickly (aka speed read) was noticeably poor even at age 10. And my ability to quickly adapt from dark to light and recognize faces was compromised by age 30 although my vision was still better than 20/100.

It seemed the only way to get the answers was to try this myself. Easier said than done; only 12 participants would be included in this Phase I/II trial. I really had no illusions that I would be accepted into this trial but wanted to go through the motions and see how far it went in order to blog about the process.

The first thing I did was visit www.clinicaltrials.gov and search for all the current trials for Stargardt Disease. I found the ACT trial and read the eligibility, inclusion, and exclusion criteria.  I didn't want to waste anyone's time but I didn't see anything that would exclude me. I showed the study to my ophthalmologist at my yearly visit and he agreed. I had the closest participating institute fax the required form to his office. There was a lot more to it, but that got the ball rolling. Through a series of luck, timing, and hard work, the stars aligned perfectly, and I overcame what appeared at first to be the logistical nightmare of my life.

But a nightmare it was not. I am a procrastinator at heart, but untrue to form, I was totally ready and prepared for this a full week or so before it all happened. Though in retrospect, I think I had been preparing for this since 1995 when I first read about the probable cause of my failing vision - poorly equipped RPE cells in the RPE layer.

I received twice as many RPE cells (100,000 to be exact) as the first three Stargardt participants.  Amateur logic tells me that I should experience improvement in half the time. But then I remembered there are millions of photoreceptor cells that take residence in the RPE layer - will 50,000 extra fresh RPE cells really make a difference, or could the excess baggage actually have a negative effect? My positively foolish self is truly looking forward to this adventure of not knowing what's next. Just like when I ran high school cross country, I never liked to run the race course beforehand because I didn't want to know how far I had left. This time around is no different; I'm going to experience every turn for the first time. The only difference is this time, I'm taking you along for the ride.

As you can see, I’m a risk taker. And as such, I have purchased a small amount of ACT stock- but it’s my vision I’m betting on and would never let greed override my responsibility to tell the truth about my clinical trial experience. I don’t have a clue as to whether this is a good investment or not, even if my vision does improve, as this is a very early stage of the clinical trial process.

Editor’s Note: As this blog entry was in preparation, Advanced Cell Technology announced that their eleventh clinical trial patient had been treated, this one the fourth patient in their dry AMD clinical trail, and also the first of the second cohort (with 100K RPE cells) in that trial. The patient was treated by Dr. Regillo at Wills Eye Institute.

Iluvien Update 7: Alimera Sciences to Re-File for FDA Approval of Iluvien for Chronic DME

Since my last update in April (Update 6), when the first country, Austria, of an anticipated seven European Union country market approvals was announced, four additional EU approvals have occurred, bringing the total of approvals to five – with Austria, France, Portugal, Germany, along with the United Kingdom. Only Italy and Spain remain of the original seven EU countries where approvals were expected.

As I first reported back in November 2011 (Update 4), the FDA had turned down Alimera’s resubmitted NDA application for approval, stating that questions remained based on the data previously submitted, about the adverse effects (basically a higher risk of cataract formation and raised intraocular pressures) and that these were not offset by the benefits demonstrated (basically up to three years of relief of the symptoms of diabetic macular edema) and that Alimera would have to conduct further tests to prove that its product was safe and effective for the proposed indication.

I thought that this was the end of the line for possible approval in the United States. But, apparently, I have been proven wrong.

I learned today, in a news release from pSivida, Alimera’s licensor, that Alimera Sciences has indicated its intention to resubmit its application for Iluvien for diabetic macular edema (DME) to the FDA.

Based on a recent meeting with the FDA, Alimera intends to use data from Alimera's two previously completed pivotal Phase III clinical trials (FAME Study).

pSivida expects the resubmission to address the issues raised by the FDA in its November 2011 Complete Response Letter (CRL) and in its recent meeting with Alimera.

pSivida anticipates the resubmission will focus on the population of patients with chronic DME considered insufficiently responsive to available therapies, the same indication for which regulatory approval for Iluvien has been granted in various EU countries. Alimera has not reported an expected time for resubmission.

"We are very pleased at this development in the U.S. in addition to the recent marketing authorizations in Austria, France, Germany, Portugal and the U.K.," said Dr. Paul Ashton, President and CEO of pSivida.

Under a collaboration agreement with Alimera, pSivida granted Alimera an exclusive worldwide license to manufacture and sell Iluvien for the treatment and prevention of eye diseases in humans other than uveitis. Alimera agreed to fund all development costs, pay pSivida a $25 million milestone payment upon FDA approval of Iluvien and 20% of any net profits, as defined, on sales of Iluvien by Alimera.

Stay tuned for any further developments.


Editor’s Note: There is an excellent discussion about the FDA’s turndown of Alimera Sciences’ application to approve Iluvien last November in the current (July/August) issue of Retina Today. This is timely, especially in light of Alimera’s decision to re-file their application, this time for chronic DME.

Three noted retinal specialists, Robert L. Avery, MD; David M. Brown, MD; and Baruch D. Kuppermann, MD, PhD, provide their perspectives regarding Iluvien.

To read their views, please follow this link.