Article Date: 4/1/2009

OPKO Terminates Wet AMD Trial
SUBSPECIALTY NEWS

OPKO Terminates Wet AMD Trial

A Second Setback for siRNA Drugs

JERRY HELZNER, SENIOR EDITOR

■ OPKO Health has announced that, following the recommendation of the Independent Data Monitoring Committee (IDMC), it has decided to terminate its phase 3 clinical study of bevasiranib, a first-in-class small-interfering RNA (siRNA) drug for the treatment of wet AMD.

The progress of bevasiranib through clinical trials had been closely watched in the drug research community, as it represented the first siRNA drug to reach a pivotal phase 3 trial. Bevasiranib moved into its phase 3 trial after an encouraging phase 2 study that showed good duration of response. OPKO designed the phase 3 study in an effort to demonstrate that bevasiranib could be effective as maintenance therapy after initial treatment with ranibizumab. Bevasiranib was also named one of the top five most promising drugs entering phase 3 clinical trials during the third quarter of 2007 by Thompson Scientific, which monitors developments in the pharmaceutical industry.

Another siRNA drug for wet AMD (siRNA-027) developed by Allergan and SIRNA Therapeutics, which is now a subsidiary of Merck, completed a phase 2 trial last summer and did not meet the efficacy hurdle though it had no safety issues. Although Allergan and Merck have ended this collaboration, new targets for this compound may be found. That means that only Pfizer and partner Quark are still pursuing a siRNA treatment for retinal diseases.

The two disappointments could represent a setback to the future of siRNA eye drugs. SiRNAs have been widely touted as the next big category in drug development. Two US researchers won the Nobel Prize in Physiology/Medicine in 2006 for their discovery of siRNAs.

Although preliminary data showed activity of bevasiranib when used adjunctively with Genentech's Lucentis, review of the data by the IDMC indicated that the trial, as structured, was unlikely to meet its primary endpoint. There were no systemic safety issues identified and local ocular safety was generally unremarkable.

"While we are clearly disappointed with the preliminary results of this fully enrolled study, the indications of activity are encouraging and we look forward to fully analyzing the data in the coming weeks," said Phillip Frost, MD, chairman and CEO of OPKO Health. "We remain committed to the continued development of our siRNA portfolio targeting Vascular Endothelial Growth Factor, including our recently announced VEGFA165b-sparing siRNA. These new proprietary siRNAs are designed to inhibit the angiogenic VEGFA165 isoform but spare the antiangiogenic VEGFA165b isoform."

IN BRIEF
New finding on "immune privilege." Scientists at Schepens Eye Research Institute have shown for the first time that a laser burn to 1 retina can cause both eyes to lose a special protective ability known as "immune privilege."
Immune privilege protects the eye without the inflammation of the body's normal immune response, which can further damage delicate eye tissue. This finding, published in the February issue of the American Journal of Pathology, has implications for treating patients with laser burns sustained in combat and in other modern settings.
The discovery is also significant because it suggests a previously unknown communication between the 2 eyes. "This deepens our understanding of the way immune privilege works," Joan Stein Streilein, PhD, principal investigator of the study and Senior Scientist at Schepens,
Immune privilege is a modification of the body's normal immune response. It protects the eye, the brain and the reproductive system without the full-blown immune response that uses inflammation to violently reject foreign tissue or invaders.
While inflammation in other parts of the body is a useful battle between immune and foreign cells, it is too aggressive for fragile eye, brain, and reproductive tissues, and, in the case of the eye, can even lead to blindness. Immune privilege, which intervenes in the battle, is also what prevents the eye from rejecting corneal transplants.

Dr. Dunn: Missions Are "Fulfilling"

He Provides Retina Care – and Removes Cataracts.

RENÉ LUTHE, SENIOR ASSOCIATE EDITOR

■ As a retinal specialist based at Florida Retina Institute in Daytona Beach, FL, William J. Dunn, MD, finds eye care missions to underdeveloped countries spiritually fulfilling.

"I feel enriched when I return from a mission," he explains of the trips he began in 2000. "Physical exhaustion but total — and I don't mean to sound trite — spiritual fulfillment."

Dr. Dunn has participated in 7 international missions, 3 to India, 1 to Grenada, and 3 to the Dominican Republic.

In addition to the spiritual satisfaction, there's also plenty of adventure to be enjoyed. "Probably the most dangerous thing I've done — and I'm a sky-diver — was a 12-hour drive in the front seat of a car to the mission site in India.

"It's like their I-95 going north out of Delhi. But it's only 2 lanes, sometimes one and a half lanes. There are semi-tractor trailer trucks, camels, elephants, rickshaws, you name it. It's unbelievable. Cars coming right at you, and at the last minute, they would switch lanes and we would avoid an accident by a fraction of an inch. They pull their mirrors in, they come so close. They don't have seat belts or shatterproof glass, so if you go through the windshield, you're done."

Once safely at the mission site, whether in India or the Dominican Republic or Grenada, this Air Force colonel, former flight surgeon, and father of 4 is faced with the problem of a limited ability to treat retinal patients. The more remote areas the missions target lack the facilities needed to surgically treat retinal disorders and the equipment required is difficult and expensive to transport. Mainly, Dr. Dunn says, he functions primarily as a comprehensive ophthalmologist, performing cataract surgery, strabismus, oculoplastics, and when needed as a retinal consultant.

Dr. Dunn examines a patient with diabetic retinopathy in the Dominican Republic.

"I would see retinal consults that local doctors would save up, as they don't have many retinal specialists in India, except in the major cities. I would help them make the decision, is it worthwhile to send this patient to the capital for treatment, or can we make the diagnosis of an untreatable condition and save the family the trouble of a long trip."

The last is an important consideration in countries where patients have few resources and the transportation system is very different from that in more prosperous countries.

"It might be a 200-mile ride. In the United States, it would take us 3 or 4 hours in a car, but 200 miles in India, at about 10 miles an hour average, would take you a long day, maybe 2 days."

On missions to the Dominican Republic through the Diocese of Orlando, FL., Dr. Dunn's insights help mission leaders decide if treatment is viable and worth the allocation of Church funds.

For a time, Dr. Dunn was able to bring a diode laser on eye care missions. "I could treat diabetics and vascular occlusive disease, similar conditions that I would treat in my own office," he says. "That laser broke down in Grenada and I'm trying to get a donated or trade-in laser that we could bring. Unfortunately, I did not have a laser for this last mission, and I had a number of diabetic patients that I could have treated." Dr. Dunn was able to bring along several vials of Avastin, which enabled him to treat patients with vascular occlusive disease.

The role he fills most often on these missions, Dr. Dunn says, is that of cataract surgeon. "I was a general ophthalmologist for 7 years before I became a retinal surgeon, so I feel comfortable with my general ophthalmology skills doing manual I/A cataract extraction — large incision." He calls it "‘80s-style surgery," performed with simple equipment that the surgeons bring along themselves.

"It is exciting to be able to contribute and make a difference in their lives! It's very common to see to patients who've basically been ignored medically for most of their lives," Dr. Dunn says. "The gratitude on their faces the next day when they can see again is reward enough for our efforts."

Endophthalmitis Rare After Cataract Surgery

Large Study Finds Few Infections.

■ A large study by Canadian researchers reported in the March issue of Ophthalmology has found that endophthalmitis continues to be rare following cataract surgery.

That means fewer late-night calls for retina specialists, who are almost always brought in on an emergency basis when endophthalmitis is a possibility. Immediate referral to a retina specialist is called for when endophthalmitis is suspected or identified. Though the treatment strategy can vary, vitreous tap for culture and sensitivity followed by the intravitreal injection of vancomycin and amikacin or ceftazidime is the most common regimen. Subconjunctival and/or systemic antibiotics are sometimes also administered.

Because cataract surgery techniques and patient selection criteria have evolved rapidly in the past several years, the researchers wanted to learn whether infection risks were changing as a result. The largest previous study, completed in 2001 using records of a half-million United States Medicare cataract patients, had documented very low infection rates.

Chaim M. Bell, MD, PhD, and Wendy Hatch OD, MSc, of the University of Toronto and their colleagues reviewed records for more than 440,000 consecutive cataract surgeries performed in surgical facilities in Ontario, Canada, between April 2002 and March 2006. Facilities where more than 50 cataract surgeries were performed annually were included. To estimate infection rates, the study tracked postoperative procedures to treat suspected infections that occurred within 14 days of cataract surgery.

The overall rate of suspected acute endophthalmitis was 1.4 per 1,000 surgeries. Patients who required procedures to correct ruptures of their lens capsule during their cataract surgery were about 10 times more likely to develop suspected infection but fewer than 1 in 200 sustained such a rupture. The highest rate of suspected endophthalmitis occurred in patients over age 85 (2.18 per 1,000). Men were at somewhat higher risk than women (1.7 vs. 1.19 per 1,000). No differences in rates were found between patients living in rural vs non-rural settings, nor were differences noted among socioeconomic groups. No upward or downward trend in suspected endophthalmitis related to cataract surgery was evident during the study period.

OMISSION
In the March 2009 issue of Retinal Physician we neglected to give credit to Martin Charles, MD, for Figure 2 in 'Focus On ...' article. We would like to thank Dr. Charles for use of this figure and apologize for not acknowledging him in the issue.

IN BRIEF
VEGF-Trap in DME trial. Regeneron has recently initiated a phase 2 study using VEGF-Trap Eye to treat diabetic macular edema. The study, known as DA VINCI, is a double-masked, randomized, controlled trial that is evaluating 4 different VEGF Trap-Eye regimens vs laser treatment.
The study will be enrolling approximately 200 patients in the US, Canada, European Union, and Australia. The patients in the study will be treated for 52 weeks followed up by 6 additional months of safety evaluation. The primary efficacy endpoint is the change in best corrected visual acuity from baseline to week 24.
Roche to acquire Genentech. After months of wrangling, Roche has agreed to buy the 44% shares of biotech giant Genentech it does not already own in a $46.8 billion "friendly" takeover. Genentech is the developer of Lucentis, the market-leading treatment for wet AMD.
The deal calls for a $95 cash payment for each outstanding Genentech common share.
Roche has been attempting to gain full ownership of Genentech for months. Its first bid of $89 per share was rejected by Genentech last summer. With the stock market in free fall in late January, Roche lowered its bid to $86.50 per share, while going directly to shareholders and seeking to bypass Genentech's board.
Roche said the combined company would be the seventh-largest US pharmaceutical company in terms of market share and generate about $17 billion in annual revenues with a payroll of around 17,500 employees in the US pharmaceuticals business alone. Combined US operations will be headquartered in South San Francisco, CA, where Genentech is based.

Data on AMD Therapies Revealed at RPS

■ Attendees of last month's Retinal Physician Symposium, held March 25-28, were among the first to learn how several investigational therapies fared in early trials. Notable findings include:

Implant for Dry AMD. An intraocular implant containing human cells genetically modified to secrete ciliary neurotrophic factor (CNTF) slowed vision loss in dry AMD patients with geographic atrophy (GA), according to phase 2 clinical trial data presented by Jeffrey Heier, MD. The implant (NT-501, Neurotech Pharma ceuticals) delivers CNTF in a controlled, continuous basis via proprietary encapsulated cell technology, bypassing the blood-retinal barrier. In his presentation, Dr. Heier described the device as "an implantable protein factory" that allows for longterm, controlled drug delivery.

CNTF, secreted extracellularly in response to injury, has been proven in animal models to be capable of a neuroprotective effect. In this multi-center, randomized, double-masked, sham-controlled study, 51 subjects received either a high- or low-dose NT-501 implant or a sham in 1 eye only and were assessed for BCVA change using the ETDRS protocol. Patients were also evaluated for change in GA size and macular volume.

The high dose of NT-501 stabilized BCVA at 12 months, with 96.3% of treated patients losing fewer than 3 lines of vision vs. 75% of sham-treated patients. No increase in vision was observed, however, likely due to existing photoreceptor damage. There were no NT-501 associated serious adverse events and both the implant and the surgical procedure were well tolerated. "This was a proof-of-concept study in essence, so safety is most important," Dr. Heier noted. Though statistical significance was not shown in change in atrophy, the change in the high-dose patients was significantly less than the low-dose group. However, the sham and high-dose groups were similar, which was somewhat surprising, since studies have shown the average change in GA to be significantly greater than the sham group. "The positive acuity change and increase in macular volume merit further investigation, and future studies are in design," Dr. Heier said.

RNA interference. Small interfering RNA (siRNA) molecules can silence any gene, provided its nucleo tide sequence is known, and the investigational agent RTP-801 from Quark Biotech and Pfizer, Inc. is a leading candidate for use in AMD. The drug arrests neovascularization through traditional VEGF blockade as well as by stimulating the anti-angiogenic pigment epithelial growth factor and decreasing production of angiogenic factors such as protein kinase C-beta.

RTP-801's phase 1 data in wet AMD were presented by Peter Kaiser, MD. The study involved two strata of subjects: the first included patients who had failed prior therapy and were unlikely to show improvement, with visual acuity below 20/200; the second group had the potential to show improvement, with VA up to 20/100 and prior history of response to anti-VEGF therapy. It was in this second group that investigators hoped to observe any signal in terms of efficacy.

Dr. Kaiser noted that 3 of the 27 subjects (11%) in the stratum 2 group gained 3 lines of vision and about 90% had less than 15-letter loss of vision. "These are reasonable results for a phase 1 study," Dr. Kaiser said, adding that "the safety was excellent." While 19% of patients had an adverse event of some sort, the majority were related to the injection itself rather than the drug. No dose-limited toxicity was reached. Because of the efficacy signal noted, a phase 2 study will proceed, he said. Researchers are excited by "a possibility of reduced apoptosis within the retina and decreased inflammation," said Dr. Kaiser, who also suggested it may hold potential for use in combination with existing anti-VEGF agents.

Epimacular Brachytherapy. Several clinical cases from the MERITAGE study using the epimacular brachytherapy device from NeoVista, Inc. — which delivers a targeted radiation dose of strontium-90 to the neovascular membrane while sparing adjacent structures — were presented by lead US investigator Pravin Dugel, MD.

The goal of the study is to assess whether Epi-Rad therapy can reduce the treatment burden in patients with persistent subretinal fluid requiring chronic anti-VEGF injections. The inclusion criteria were fairly strict. "We wanted to make sure anti-VEGF treatment was given as much of a chance as possible," Dr. Dugel said. The study requires an induction period of 3 consecutive injections and a persistent treatment period of at least 5 additional injections over 12 months or 3 more injections over six months.

After presenting an array of early outcomes data from individual cases, Dr. Dugel concluded that the number of injections prior to enrollment "seems to be a bigger determinant than baseline acuity of whether they'll improve or not." Given that the primary endpoint is reduction of injection frequency and maintenance of visual acuity from the pre-study phase, observation of VA improvement in many cases was "a pleasant surprise" and could be evidence of a possible synergistic effect between radiation therapy and anti-VEGF agents.

Look for additional data and a full report on RPS next month. RP



Retinal Physician, Issue: April 2009