Stem Cell Trials Begin at UCLA
Stargardt's and dry AMD targeted
■ Advanced Cell Technology, Inc. recently announced the dosing of the first patients in each of its two phase 1/2 clinical trials for Stargardt's macular dystrophy and dry AMD using retinal pigment epithelial cells derived from human embryonic stem cells (hESCs). The patients were treated by Steven Schwartz, MD, who is the Ahmanson professor of ophthalmology at the David Geffen School of Medicine at UCLA and retina division chief at UCLA's Jules Stein Eye Institute.
Both patients successfully underwent the outpatient transplantation surgeries and recovered uneventfully.
Both the Stargardt's trial and the dry AMD trial will enroll 12 patients each, with cohorts of three patients each in an ascending dosage format. Both trials are prospective, open-label studies designed to determine the safety and tolerability of hESCderived RPE cells following subretinal transplantation into patients with Stargardt's and dry AMD at 12 months, the studies' primary endpoint.
“This first treatment milestone is welcomed by scientists, stem cell advocates and patients hoping for cures,” said Gary Rabin, interim chairman and chief executive officer of ACT. “The two trials could not have started any smoother, and we are very pleased to announce that the procedures went well. The dosing of the first patients … opens the doors to a potentially significant new therapeutic approach to treating the many forms of macular degeneration. We believe that these procedures represent a key step forward in therapeutic stem cell research, and the capacity to treat a variety of devastating diseases.”
Dr. Schwartz, the principal investigator, explained, “One patient in each clinical trial — the Stargardt's trial and the dry AMD trial — has undergone surgical transplantation of a relatively small dose (50,000 cells) of fully differentiated retinal pigment epithelial cells derived from human embryonic stem cells. Early indications are that the patients tolerated the surgical procedures well. The primary objective of these phase 1/2 studies is to assess the safety and tolerability of these stem cell-derived transplants. We will be carefully monitoring our patients over the course of the trials.”
Delay in Eylea AMD Approval Process
But drug moves ahead in CRVO and DME.
■ Regeneron Pharmaceuticals has been notified by the FDA that the agency has extended its target date to complete the priority review of the Eylea Biologics License Application (BLA) for the treatment of wet AMD to Nov. 18, 2011, a three-month extension from the original action date. The news came as a surprise, as most industry analysts had anticipated FDA approval of Eylea for the wet AMD indication in mid-August.
The extension is a result of the agency classifying recent responses to questions regarding the chemistry, manufacturing, and controls section of the BLA as a major amendment to the BLA. The new action date will give the agency additional time to review the information submitted.
In a conference call, the company said there were no issues causing the delay other than the mass of paperwork that the FDA must examine. The company also noted that approximately half of all drugs awarded a speedy priority review encounter some delay in the approval process. Delays strictly for procedural matters have not affected ultimate approval of these drugs.
In other Regeneron news, oneyear data for the company's phase 3 COPERNICUS study for CRVO was recently presented at the annual ASRS meeting. Previously, the company had reported six-month data showing that 56.1% of patients receiving 2 mg of Eylea monthly had gained 15 letters or more and that the average six-month gain was 17.3 letters. The average six-month vision loss with sham was 4 letters.
The one-year data is generally consistent with the earlier results, including the following key results:
► By week 52, the mean gain from baseline was 16.2 letters.
► Three-line gainers increased from 12.3% of patients at week 24 to 30.1% at one year.
► Mean injections given from week 25 to week 52 was 2.7.
► Mean time to re-injection during the second half of the study was 68 days.
► Sham-treated patients from the first six months who were then switched to active drug for the second half gained a mean of eight letters on PRN dosing.
In related news, Regeneron and Bayer Healthcare have each initiated a phase 3 study of Eylea in DME. The Bayer-led study (called VIVID-DME) will be conducted in Europe, Japan, and Australia. The study led by Regeneron (VISTA-DME) will be conducted in the US, Canada, and other countries.
In the recently completed phase 2 DaVinci study for DME conducted by Regeneron, 44 patients receiving a monthly 2 mg dose of Eylea achieved a mean visual acuity gain of 13.1 letters after 52 weeks, while 42 patients receiving a 2 mg dose every two months (following three initial monthly doses) achieved a mean VA gain of 9.7 letters in the same time period. Forty-five patients who received a 2 mg dose PRN (after three initial monthly doses) achieved a mean VA gain of 12.0 letters after 52 weeks.
|Impact of CATT Study: ASRS Audience Poll|
|At the recent ASRS annual meeting, retina specialists in attendance were asked to respond to an audience poll regarding the impact of the CATT study on their use of anti-VEGF drugs. Below is an impromptu tally of opinions from an audience several hundred attendees.|
■ Did the one-year CATT results alter your treatment of wet AMD?
64% - No, it reinforced my choice of agents.
28% - Yes, I now use more Avastin.
8% - Yes, I now use more Lucentis.
■ Did it alter your treatment/follow-up pattern?
56% - No, it reinforced my treatment schedule.
34% - Yes, I now treat more frequently.
10% - Yes, I now treat less frequently.
■ Are you worried about systemic adverse events in the Avastin cohort?
23% - Yes, I limit anti-VEGF in high risk patients.
37% - Yes, but I don't alter treatment.
40% - No, I don't worry about increased systemic risk.
Toward Safer Intravitreal Injections
Study suggests masks and silence
■ An interesting study conducted by researchers at UCLA's Jules Stein Eye Institute suggests that retina specialists can achieve a higher level of infection prevention by wearing masks and avoiding talking while performing intravitreal injections. The results of this study, designed as a simulation of real-world conditions that could be factors in the incidence of endophthalmitis, were reported recently in the Archives of Ophthalmology.
The researchers began by recruiting 15 volunteers, with each volunteer positioned over an open blood agar plate. Each volunteer then had five distinct assignments: read a five-minute script with a face mask, read a fiveminute script without a face mask, read a five-minute script with the face turned away from the plate without a face mask and stand in silence for five minutes. Each volunteer then read a five-minute script while reclined in a standard ophthalmic examination chair with an open blood agar plate secured to the forehead to simulate bacterial dispersal associated with a talking patient. Total numbers of colony-forming bacteria per plate were counted, and the bacteria were identified.
Researchers found that significantly less bacterial growth occurred in the face mask and silence conditions compared with the no face mask condition (both P< 0.001). Bacterial growth was significantly greater in the reclined condition compared with the room control (P = 0.02). Oral Streptococcal species represented 66.7% to 82.6% of bacterial colonies in the no face mask, face turned, and reclined conditions.
The researchers concluded that during simulated intravitreous injection, wearing a face mask or remaining silent significantly decreased culture plate contamination from talking. Talking from above and talking in the reclined position were associated with a significant increase in culture plate contamination.
The researchers cautioned that physicians performing intravitreous injections should be aware of these patterns of bacterial contamination, should consider either wearing a face mask or minimizing speech, and should encourage patients to minimize speech during the procedure.
The new finding “doesn't prove anything conclusively,” study author Colin McCannel, MD, told Reuters. But he added that “my advice to patients would be, until the injection is complete … minimize conversation or talking with the physician.”
|Letter to the Editor|
|Recent information that cumulative doses of hydroxychloroquine may be more toxic than suspected is useful information for rheumatologists, internists, ophthalmologists, patients, and tort lawyers.|
Overall, the new American Academy of Ophthalmology 2011 guidelines are expensive to implement, inconvenient to patients and ophthalmologists, questionably likely to improve false negatives over the 2002 AAO guidelines, and guaranteed to increase malpractice tort litigation against physicians.
The new guidelines require one of three newly mandated tests: SDOCT, mfERG, or fundus autofluorescence (FAF). Let me give readers an idea of the costs to equip just one office with one of these modalities. All prices were obtained from Kansas City ophthalmic equipment suppliers.
Multifocal ERG is not available in the Kansas City area. A new Veris mfERG will run about $32,000. Many practices now have fundus cameras; they can be upgraded for FAF for about $10,000, or a new Topcon 50 EX with FAF goes for about $14,500. We also have a TD-OCT, but that does not rise to the level of the new guidelines. An SD-OCT is priced from $46,500 to $54,500. The trade-in value of a TD-OCT is sinking like a stone. Factor in that we have eight offices, and you have some idea of the enormous expense involved to meet the new standard of care.
I practice in a three-ophthalmologist, three-optometrist office. We do perhaps three or four hydroxychloroquine screenings a week (dilated exam with refraction, color testing, and 10-2 Humphrey visual fields). We have a retina specialist on site two days per week. We have a TD-OCT, and our fundus camera does not do FAF. Thus, without buying an SDOCT or upgrading our camera to FAF, we cannot meet the new standards. If we do spend the money to get the new instrumentation, then we add up to 16 more patient encounters and special testing per month to our already overworked retina specialist. Moreover, he does not do refractions, and we cannot bill if the patient sees an optometrist or comprehensive ophthalmologist the same day.
The patient ends up with two exams per year rather than one, plus the cost of one of the three added tests. Also, patients may have to travel to one of our distant offices if we cannot afford to equip all eight offices with the newly required instrumentation. The guidelines require one of the SD-OCT, mfERG or FAF. To a trial lawyer, that means available from any ophthalmologist in your community or within a two- or three-hour drive. Do not expect to hide from liability because these technologies are not available in your office.
The 2011 AAO guidelines are said to recommend an initial baseline exam with one of the three high-technology tests; then, annual screening is recommended after five years. It is true that patients may benefit from annual screening but following the new guidelines and seeing patients five years after they start hydroxychloroquine is, in my opinion, opening oneself to great legal peril. Twelve months is the longest any patients on these medications should go without toxicity screening examination.
These new guidelines are, in my opinion and the opinions of the perhaps 20 or more ophthalmologists that I have discussed them with, regressive, impractical, expensive and fraught with malpractice liability. I would request the support of retinal physicians and your subspecialty societies in asking the AAO to rescind and revise them.
John C. Hagan, III, MD, FACS, FAAO
Editor, Missouri Medicine
Immediate Past President,
Metropolitan Medical Society of Greater Kansas City
Discover Vision Centers
Kansas City, MO
A New Self-test for Retinal Disease
More accurate than the Amsler Grid?
■ An ophthalmologist at UT Southwestern Medical Center has helped create a convenient device that lets patients who have a degenerative eye disease better track vision changes. The device may become commercially available following a 12-month clinical trial designed to confirm a recently completed eight-month trial of a prototype.
With the handheld digital device, called myVisionTrack, patients can now perform an accurate self-test in less than 90 seconds, said Yu-Guange He, MD, associate professor of ophthalmology at UT Southwestern.
“Many patients do not have timely eye exams and end up suffering preventable vision loss,” he said. “Careful self-monitoring is critical because treatment for age-related macular degeneration and diabetic retinopathy is most effective when given at precise stages in the disease's progression.”
Supplied as an app on an iPhone or iPod touch, the prototype device displays three circles on a screen, one of which is markedly different from the others. Patients cover one eye, then touch what they perceive to be the odd-shaped circle on the screen. With each click, the differentiation becomes more subtle. The test is then repeated with the other eye. Results are stored in the device so patients do not have to memorize scores. If a significant vision change is detected, patients are instructed to see their doctor.
Many patients diagnosed with — or at risk for — a degenerative eye disease have used the Amsler grid. Numerous patients using the grid, however, failed to notice subtle vision changes. By contrast, myVisionTrack's “shape discrimination” tests are twice as sensitive as the paper eye chart in detecting small changes in vision, Dr. He said.
The myVisionTrack device was produced by Vital Art and Science Inc., a Richardson, Texas-based biotech firm that recently received approval for up to $1 million from the Texas Emerging Technology Fund to develop the product. Researchers at UT Southwestern and the Retina Foundation of the Southwest tested the prototype device in an eightmonth clinical study funded by the National Institutes of Health's National Eye Institute. Forty diabetic patients diagnosed with retinopathy used the monitoring device at home each week. Their test results showed a high correlation with an ophthalmologist's reading of their retinal images, taken at the beginning, midpoint and end of the study.
|■ Infections from repackaged Avastin. Something that all retina specialists dread has occurred — twice — outbreaks of endophthalmitis due to tainted intravitreal injections. One incident has been traced to a compounding pharmacy in South Florida and another to a VA pharmacy in Tennessee.|
In early September, the FDA put out an alert stating that repackaged intravitreal injections of Avastin have caused a cluster of endophthalmitis infections in the Miami area. Earlier, four cases of endophthalmitis were reported at the veteran's facility in Nashville.
The Florida Department of Health notified the FDA of a cluster of Streptococcus endophthalmitis infections in three clinics following intravitreal injection of Avastin that was traced to a single pharmacy located in Hollywood, Fla. The pharmacy repackaged the Avastin from sterile injectable 100 mg/4 mL, single-use, preservative-free vials into individual 1 mL single-use syringes. The pharmacy then distributed the Avastin to multiple South Florida eye clinics for use in treating patients.
To date, FDA is aware of at least 12 patients in at least three of these clinics who had the eye infection. While all of these patients had visual deficits prior to their injections with Avastin, some of these patients lost all remaining vision in that eye due to the endophthalmitis. The agency and Florida health officials have continued to investigate the cause and extent of the outbreak. While the investigation is not yet complete, the common link for the infections is the pharmacy that repackaged the Avastin and the single lot of Avastin used in the repackaging.
The effects these incidents will have on the off-label use of Avastin by retina specialists are yet to be known but possible beneficiaries include Lucentis and the still-to-be approved Regeneron drug Eylea.
■ Canada approves Lucentis for RVO. Health Canada has approved Lucentis as a treatment for both types of retinal vein occlusion — BRVO and CRVO. The decision was based on data from the pivotal phase 3 BRAVO and CRUISE studies.