Stem Cells in Ophthalmology Update 10: ACT Expands Trials for Embryonic Stem Cells for Stargardt’s to the UK

In a news announcement today, Advanced Cell Technology said it had received approval to expand its stem cell treatment for Stargardt’s Macular Dystrophy to Moorfield’s Hospital in the UK.

As reported by the Guardian, “The Massachusetts-based company Advanced Cell Technology (ACT) announced the trial ... will run alongside a similar study that began in July at the Jules Stein Eye Institute at the University of California, Los Angeles.

Only one patient has been treated so far in the US trial for Stargardt's disease. The results from both studies are expected next year.”

Here is the company’s announcement:

ACT Receives Approval for First Human Embryonic Stem Cell Trial in Europe

Moorfields Eye Hospital in London is Site for Phase 1/2 Trial to Treat Stargardt's Macular Dystrophy

MARLBOROUGH, Mass. - Sept. 22, 2011 - Advanced Cell Technology, Inc., a leader in the field of regenerative medicine, announced today that it has received clearance from the U.K. Medicines and Healthcare products Regulatory Agency (MHRA) to begin treating patients as part of a Phase 1/2 clinical trial for Stargardt's Macular Dystrophy (SMD) using retinal pigment epithelium (RPE) derived from human embryonic stem cells (hESCs). ACT received similar approval from the the Gene Therapy Advisory Committee (GTAC), which has responsibility for the ethical oversight of proposals to conduct clinical trials involving gene or stem cell therapies in the U.K. The European Medicines Agency (EMA) previously granted Orphan Drug designation for the company's RPE cell product for use in treating SMD.

"This is another important milestone for ACT and for the field of regenerative medicine," said Gary Rabin, chairman and CEO of ACT. "We are pleased that the Moorfields Eye Hospital in London has agreed to participate as a site for this study as we continue to assess the capabilities of hESC-derived RPE cells to repair the retina and reduce the impact of these devastating eye diseases. We recently announced the dosing of the first patients in our Phase 1/2 clinical trials for Stargardt's macular dystrophy and dry age-related macular degeneration (dry AMD) with hESC-derived RPE cells in the U.S., and both patients successfully underwent the outpatient transplantation surgeries. (Editors Note: See Updates 8 and Update 9) Clearance from the MHRA to begin an SMD trial in the U.K. is the first step in our European clinical trial program. Europe not only represents the world's second-largest pharmaceutical market, but it is also home to some of the best eye hospitals and surgeons in the world. Building international relationships around our clinical programs, such as with Professor James Bainbridge at Moorfields Eye Hospital is very important to our strategy of developing new regenerative medicine therapies."

Stargardt's Macular Dystrophy affects an estimated 80,000 to 100,000 patients in the U.S. and Europe, and causes progressive vision loss, usually starting in people between the ages of 10 to 20. Eventually, blindness results from photoreceptor loss associated with degeneration in the pigmented layer of the retina, the retinal pigment epithelium. The first patient to be treated in the U.S. with stem cell-derived RPE cells was a young woman who was already legally blind as a consequence of this disease. This newly-approved clinical trial in Europe will be a prospective, open-label study designed to determine the safety and tolerability of RPE cells derived from hESCs following sub-retinal transplantation to patients with advanced SMD, and it is similar in design to the FDA-cleared U.S. trial initiated in July.

"This is the first time an embryonic stem cell trial has ever been approved anywhere else in the world," said Robert Lanza, M.D., ACT's chief scientific officer. "Stargardt's disease is currently untreatable, and is one of the leading causes of juvenile blindness in the world. Collectively, degenerative eye diseases afflict over 25 million people in the U.S. and Europe alone. These diseases have a devastating impact on patients and their families, which has been a strong motivating factor for developing this new treatment. In Stargardt's disease, the loss of RPE cells in the patient's macula causes a loss of photoreceptors - the cones and rods with which we see - leading to blindness. We believe that transplanting new, healthy RPE cells may provide an effective treatment for SMD and perhaps other macular degenerative diseases such as dry AMD. We are excited to start these trials in Europe, and look forward to analyzing the data we continue to collect in our ongoing trials to determine the engraftment and function of the transplanted RPE cells."

The trial will be led by Professor James Bainbridge, consultant surgeon at Moorfields Eye Hospital and Chair of Retinal Studies at University College London.

"Stargardt's disease is a form of macular degeneration that causes disabling loss of sight in young people and is currently untreatable," said Professor Bainbridge. "There is real potential that people with blinding disorders of the retina including Stargardt's disease and age-related macular degeneration might benefit in the future from transplantation of retinal cells. The ability to generate retinal cells from stem cells in the laboratory has been a significant advance and the opportunity to help translate such technology into new treatments for patients is hugely exciting. Testing the safety of retinal cell transplantation in this clinical trial will be an important step towards achieving this aim."

About Macular Degeneration and SMD

Degenerative diseases of the retina are among the most common causes of untreatable blindness in the world. As many as 30 million people in the U.S. and Europe suffer from macular degeneration, which represents a $25-30 billion worldwide market that has yet to be effectively addressed.

Avastin/Lucentis Update 49: A Follow-up on Infections from Intravitreal Injections

In my last posting (Avastin/Lucentis Update 48), I wrote about the problems with Avastin injections, that appeared to be caused by non-sterile/non-aseptic techniques during re-packaging Avastin from 4 ml bottles into much smaller doses (0.05ml) in tuberculin syringes.

A colleague, who is a compounding pharmacist, pointed out to me that other things can cause contamination of the eye during intravitreal injections besides using non-aseptic techniques during aliquoting and re-packaging of Avastin into injectable syringes.

He sent me a copy of a report from Medscape Medical News that was published online following a meeting of the American Academy of Ophthalmology and Middle East Africa Council of Ophthalmology 2010 Joint Annual Meeting, held during last year’s AAO Meeting.

Here are excerpts from that report:

Intravitreal Injections Expose Patients to Streptococcus More Often Than Eye Surgery

Kathleen Louden
October 20, 2010
Medscape Medical News

Streptococcus is isolated much more frequently from endophthalmitis cultures after intravitreal injection (IVI) of antivascular endothelial growth-factor agents than after ocular surgery, results of a meta-analysis show.

Ophthalmologists should consider using additional sterile techniques during these injections to prevent exposing patients to the sight-threatening complication of streptococcal endophthalmitis, said study author Colin McCannel, MD, associate professor of ophthalmology from the Jules Stein Eye Institute at the University of California at Los Angeles.

"If we can prevent some of the worst cases of endophthalmitis, I think it's worth the effort," Dr. McCannel told Medscape Medical News.

To confirm his impression that reports of Streptococcus organisms seemed more frequent than should be expected after IVI, Dr. McCannel analyzed the American medical literature from 2005 through 2009. He found 16 articles that reported the causative organism in post-IVI endophthalmitis. As expected, endophthalmitis was rare, occurring in 54 of 105,531 injections. Only 26 were culture-positive, according to the abstract. Most of the causative organisms were coagulase-negative Staphylococcus, he said.

However, cultures yielded Streptococcus organisms 30.8% of the time (8 of 26), which Dr. McCannel said is "3- or 4-fold higher" than the incidence reported in the literature for acute postoperative endophthalmitis. The postoperative incidence of streptococcal endophthalmitis ranges from 0% after vitrectomy to 8.2% to 9% after cataract surgery, he reported.

Likely Source of Infection

This finding led him, he said during an interview, to do "some detective work" to try to find the possible source of these streptococcal infections. He found several studies in the anesthesia literature reporting streptococcal meningitis after dural puncture, a procedure that, according to Dr. McCannel, has a working distance between physician and patient similar to that of IVI. Analysis found that the causative organisms in most of those cases came from the treating physician's oral flora, which was aerosolized during talking.

Consequently, the Centers for Disease Control and Prevention in Atlanta, Georgia, recommended in 2007 that spinal procedure operators wear a surgical mask during the procedure (MMWR Morb Mortal Wkly Rep. 2010;59:65-69).

Ophthalmologists "often have to give directions to the patient during injections, and sometimes there is small talk," Dr. McCannel said. "The patient's eye is probably being showered with these microscopic droplets. We may be contaminating the injection field or the needle."

Recommendations

If other studies validate his findings, the ophthalmic community should decide whether to recommend wearing a surgical mask during IVI, he said. He told the audience that he does not wear a mask because "it would be burdensome to take it on and off" during the brief injections.

Another precautionary strategy that Dr. McCannel suggested was to avoid talking, coughing, or sneezing during the injections. He said he asks his ophthalmic technicians to instruct the patient before the procedure that "the injection is not the time to ask questions" and to refrain from talking. If he needs to instruct the patient, he said he speaks away from the patient.

A panelist at the session who did not participate in the study, Joan W. Miller, MD, said in an interview that the study findings have the potential to change clinical practice. Dr. Miller, professor and chair of ophthalmology at Harvard Medical School in Boston, Massachusetts, said she will consider changing her IVI techniques to try to prevent the spread of Streptococcus.

"Not talking on the [injection] field is probably sufficient precaution," she told Medscape Medical News.



My friend, the compounding pharmacist, went on to say,  “I wish we had more visibility into what [really] happened in TN and FL and the pharmacies that prepared those compounds. It is even more critical that physicians look to do their diligence when choosing a pharmacy to provide these sterile compounds to patients. Because of our strict quality control and assurance procedures we have created an environment that focuses on quality.”

“As you may be aware OMIC, the ophthalmology insurance carrier, has been recommending to physicians that the best practice is to seek out compounding pharmacies that have been accredited by PCAB, the Pharmacy Compounding Accreditation Board.  Being accredited by PCAB gives confidence to physicians and consumers that products are prepared in accordance with the United States Pharmacopeial Convention's standards. Chapter 797 of the USP clearly outlines the facility, environment and testing necessary to provide sterile compounded products.  Without an accreditation body like PCAB, there is no reliable third-party verification that a pharmacy meets the USP 797 standard.”