Article Date: 3/1/2012

CABERNET Study Fails to Meet Key Endpoint
SUBSPECIALTY NEWS

CABERNET Study Fails to Meet Key Endpoint

Setback for radiation as wet AMD therapy.

Jerry Helzner, SENIOR EDITOR

Best results were achieved when the tip of the probe touched the retina.

■ A pivotal study to determine if radiation (epimacular brachytherapy) can be effective in combination with anti-VEGF therapy to reduce the number of intravitreal injections required to treat wet AMD did not meet its primary endpoint at two years.

NeoVista’s CABERNET study, with a 302-patient treatment arm and a 155-patient control arm of patients receiving only ranibizumab, did not achieve its endpoint of a non-inferiority margin of 10%. At two years, the treatment group required an average of about six injections and demonstrated a mean 2.5 letter vision loss while the ranibizumab-only patients were given an average of 11 injections and achieved a mean 4.4 letter gain at 24 months. All patients in the study were treatment-naïve.

The non-inferiority margin was not achieved despite the fact that some subgroups did well and gained vision with fewer injections when treated with the radiation/ranibizumab combination.

The patients in the treatment arm received 24 Gy of radiation along with two initial monthly ranibizumab injections. The ranibizumab-only cohort received three initial monthly loading doses of the drug with mandatory quarterly injections thereafter, essentially a modification of the original PIER trial protocol. Retreatment with ranibizumab was permitted in both groups if specific criteria of vision loss, increased macular thickness and/or confirmed new neovascularization were met during the monthly follow-up visits.

Pravin U. Dugel, MD, who served as chief investigator for the study, reported the data at the recent Bascom Palmer 50th anniversary conference. He noted that two major weaknesses in the study design (which was developed in 2006) were studying treatment-naïve patients and the is sue of probe placement.

In regard to treatment-naïve patients, he said that in retrospect the radiation/ranibizumab combination may have been of greater benefit to more “difficult” patients who had been treated with anti-VEGF drugs and then required an alternative second-line therapy.

With regard to probe placement, Dr. Dugel told Retinal Physician that the best results of the radiation were achieved when the tip of the probe touched the retina. He said the importance of probe placement should have been emphasized in the protocol.

“The study was worth doing,” Dr. Dugel said. “The results are what they are.” He said that although some subgroups of patients definitely benefited from the radiation/ranibuzumab combination, “at this time, we cannot consistently identify the patients who may benefit. Therefore, it is important to present the data as it is, with absolute transparency.”

Dr. Dugel said that results of two other studies of epimacular brachytherapy — MERITAGE and the current MERLOT trial — will need to be taken into account when assessing the possible benefits of the radiation/ranibizumab combination therapy.

Epimacular brachytherapy is currently approved in all markets that accept a CE mark.

Eylea is Off to a Fast Start

But some adverse events reported.

■ Regeneron said it now expects much higher 2012 sales volume for its newly approved wet AMD drug Eylea than it first estimated. The company now forecasts 2012 US Eylea sales of $250 million to $300 million as opposed to an initial prediction in the $140 to $160 million range.

But Regeneron President and CEO Leonard S. Schleifer, MD, PhD, also said that there have been 14 cases of adverse events consistent with sterile endophthalmitis and a single case of culture-positive endophthalmitis reported to Regeneron with the use of Eylea since launch.

“This translates to a rate of 0.05% per injection, similar to that which we’ve seen in our clinical trials and within the range that has been reported with other anti-VEGF agents,” noted Dr. Schleifer. He said that 11 out of the 14 cases of sterile endophthalmitis were reported by a single (Connecticut) group practice and nine of the cases were accounted for by a single physician within this practice. The cases could not be traced to a single lot of drug nor to a single delivery of commercial vials.

“Excluding this one practice, the rate of intraocular inflammation reported to Regeneron following Eylea was approximately 0.01%, or 1 in 10,000,” said Dr. Schleifer. “We are working closely with the practice involved to better understand this cluster and are in the process of disseminating the information we have learned to retinal physicians. We have informed the FDA as per the normal course.”

Dr. Schleifer said the company does not believe, given the data available, that Eylea is responsible for the single cluster.

Because all of the trials for Eylea in wet AMD were conducted with treatment-naïve patients, the retina community is quite interested to see results with patients who are currently being switched from Lucentis or Avastin to Eylea. Data on this subset of patients is only being gathered in the last few months since Eylea was approved.

All 11 of the incidents reported by the Connecticut practice involved switched patients, though many other switched patients had no problems.

“We are getting real-world experience on [switched patients] since the launch,” a Regeneron spokesman told Retinal Physician. “I don’t believe we did any trials in that setting. We have made public comments that we are learning from the doctors that many of the patients they have been putting on Eylea since the launch in November are switchers — patients who did not do well on Lucentis.”

Vitreous-Retina-Macula Consultants of New York is currently conducting a study of patients switching from Lucentis or Avastin to Eylea and expects to report on their findings in April.

Fellows Forum Combines Learning and Fun

Dr. Allen Krieger delivers the guest lecture.

The Fellows Forum faculty ready for the annual bowling tournament. From left to right, Drs. Eliott, Heier, Chow, Hassan, Krieger, Ferrone, Awh, Kaiser and Holekamp.

■ The 12th annual Retina Fellows’ Forum was held January 27-29 at the Westin River North in Chicago. Seventy-five North American fellows participated in an educational and social program that has become a much-anticipated fixture of the final year of vitreoretinal training.

As in past years, the fellows spent considerable time in the lecture hall with a panel of volunteer faculty, led by Course Director David Chow, MD, and co-directors Carl Awh, MD and Tarek Hassan, MD. Dean Eliott, MD, Phil Ferrone, MD, Jeff Heier, MD, Nancy Holekamp, MD, and Peter Kaiser, MD, completed the faculty.

The meeting began on Friday evening with an AMD symposium and sessions on diagnostic instrumentation and pediatric retina. The “Faculty Debates” pitted the faculty against each other to argue the merits of Avastin, Eylea and Lucentis and the best method of primary retinal detachment repair (pneumatic retinopexy vs. scleral buckle vs. vitrectomy). Topics were assigned to the faculty, who relied upon clinical data, personal experience and (most effectively) humor to defend their positions.

A Friday evening reception and dinner provided the first opportunity for the “graduating class” of 2012 fellows to socialize with their peers, the faculty and representatives from industry. Saturday offered a full day of panel-driven discussions on diabetic retinopathy, retinal vascular occlusion, trauma, macular surgery, new devices, “News You Can Use” and a “Real World” session on career and lifestyle management.

The Distinguished Guest Lecture was delivered by Allen E. “Buzz” Krieger, MD, of the UCLA Jules Stein Eye Institute. Dr. Krieger educated and inspired the audience with his talk titled “Scenes from a Practice.”

Bausch + Lomb provided essential support as the major sponsor of the event. Sixteen additional companies representing a cross-section of devices and services important to vitreoretinal practice provided financial support and presented updates to the group about their businesses.

The Bausch + Lomb Research Award went to Dr. Alok Bansai from Wills Eye Hospital in Philadelphia for his paper, “Optic Neuropathy following Vitrectomy for Retinal Detachment: Clinical Features and Analysis of Risk Factors.” Dr. Bansai will present his paper at the 2012 Annual Meeting of the American Society of Retina Specialists in Las Vegas as a specially recognized lecture.

The meeting concluded with dinner, an informal awards ceremony and the 7th Annual Retinal Fellows’ Forum Bowling Tournament. Fellows and corporate representatives were divided into teams captained by the faculty.

Carl Awh’s team emerged victorious, aided in no small measure by the presence of Gene Metzger of Volk Optical, who bowled the high score of the evening.

The 13th Annual Retina Fellows Forum will be held in Chicago on Friday, Jan. 25 through Saturday, Jan. 26, 2013.

In addition to B+L and Genentech, corporate support for this year’s Retina Fellows’ Forum was provided by the following: Alcon, Allergan, Arctic Dx, Carl Zeiss Meditec, Dutch Ophthalmic, Insight Instruments, Iridex, Keeler Instruments, MedOne Surgical, Optos, QLT Ophthalmics, Regeneron Pharmaceuticals, Synergetics, ThromboGenics and Volk Optical.

Retina Fellows Assess Their Specialty

Anti-VEGF greatest advance; dry AMD biggest challenge.

■ A survey of retina fellows attending the recent Fellows Forum indicates that they overwhelmingly view anti-VEGF therapy for retinal disease as the greatest advance of the last decade in their specialty, while they also see an effective treatment for dry AMD as the biggest current unmet medical need.

In addition, a majority of the fellows said they chose to pursue a career in retina because it offers a combination of medical and surgical practice in a unique subspecialty with interesting pathology. Many also cited opportunities for research as a key element in making their choice.

The survey was conducted by Retinal Physician in cooperation with Fellows Forum and Medical Conference Planners, Inc., which is responsible for meeting services.

Following are the survey questions and representative responses.

What are the factors that led you to choose retina as your specialty?

► “Ophthalmology was the most interesting field to me during medical school. As I learned more about ophthalmology, I realized that retina encompassed all of what attracted me to ophthalmology.”
► “Enjoyed type of surgeries. Mix of clinic and operating room. Found ocular disease to be fascinating.”
► “Challenging cases, wide variety of surgical techniques, less overlap with optometric scope of practice. I also watched a macular hole repair as a medical student and saw the outcome. I was impressed by the delicate surgery involved and the gratitude that the patient showed.”
► “The combination of surgery, clinic and research.”
► “A retina surgeon is trained to do just about everything as it relates to ophthalmology. Other than complex orbital cases, a retinal surgeon rarely needs to rely on other physicians for treatment of ophthalmic conditions.”
► “Enjoy the diversity of retinal issues and seeing systemic manifestations of disease in the retina. Every retinal case is different, whereas cataract cases are the same over and over again.”
► “Enjoyed the surgeries, patient population and pathology most.”

What are your major areas of interest in retina (research, group practice, solo practice)?

► “Group practice with a strong academic interest.”
► “Translational research/surgery/innovation”
► “Research and academia”
► “I will be joining a group, retina-only private practice. As such, I am interested in advancing my surgical and medical retina skills in an efficient private practice setting. Also interested in becoming involved with clinical research. Would also like to teach residents and students periodically. Am also interested in medical mission trips around the world on occasion (ie. ORBIS).”
► “Academics that allows for research time.”
► “Group practice with a strong academic interest.”

What are your major goals in your chosen area of interest?

► “Developing novel therapeutic modalities for pathologic myopia.”
► “To build a successful practice and volunteer in the future.”
► “Be a leader in a specific area (ie: research or surgery).
► “Quality patient care”
► “Train the next generation of retina specialists and make a lasting contribution to the field.”
► “Delivering excellent medical care to patients.”
► “To be active clinically, surgically, and have my own lab.”

In what areas of the retina specialty do you see the most potential for exciting new advances?

► “PVR prevention”
► “True therapies for retinal disease (vs temporizing measures such as anti-VEGF)”
► “Imaging”
► “Cell based therapy, novel drug delivery, gene therapy.”
► “Medical retina, particularly pharmacotherapeutics such as longer acting anti-VEGF or alternatives to anti-VEGF.”
► “Dry AMD”
► “Imaging, AMD, diabetic retinopathy”
► “Dry AMD, retinal implants, stem cell and gene therapies.”

What do you believe is the greatest current unmet need in retina care?

► “Pathologic myopia”
► “PVR treatment”
► “Better care for financially disadvantaged patients with diabetic retinopathy.”
► “Dry macular degeneration. No treatment and little available in terms of prevention.” (Many survey respondents mentioned dry AMD as the greatest unmet need)
► “Lack of treatment for some hereditary diseases that result in severe vision loss.”
► “Low Vision”
► “Our lack of effective treatment for proliferative vitreoretinopathy is a major unmet need.”

What do you see as the most important new developments in retina care in recent years?

► “Anti-VEGF, smaller-gauge vitrectomy”
► “Anti-VEGF use for diabetic macular edema and macular edema associated with CRVO/BRVO.”
► “OCT”
► “Anti-VEGF therapy, gene therapy”
► “Imaging and medical treatment of AMD.”

In what ways has fellowship training met (or fallen short) of your expectations?

► “Need more scleral buckling experience.”
► “Fellowship has met all my expectations. I am treated like a peer, which is the first time in my medical education that this has happened. I have received excellent training and I feel prepared to care for patients with vitreoretinal diseases.”
► “Lack of real-world training”
► “Less research-oriented mentorship than hoed for.”
► “Surpassed my expectations in breadth of training and ability to learn difficult surgical skills.”
► “It has met my expectations of being trained to handle basic retina cases, but I still do not feel comfortable with complex PVR cases and TRD cases.”
► “Have been very satisfied with my training. Have been somewhat surprised by the wide array of procedures I have learned over the past year and a half, and all the medical retina knowledge I have attained. At the same time, I look forward to continuing to learn over the course of my career and humbly understand that training in the field of retina is truly never over.”
► “I feel competent in bread/butter retina; have not had much ROP or Tumor experience.”
► “Exceeded clinical and surgical expectations, great volume and variety of patients.”

VMA Drug Earns Priority Review

ThromboGenics cites pivotal trial data.

■ ThromboGenics NV announced that the FDA has granted priority review status for ocriplasmin intravitreal injection, 2.5 mg/mL, for the treatment of symptomatic vitreomacular adhesion (sVMA) including macular hole. Priority review is normally completed within six months.

Ocriplasmin (microplasmin) is a truncated form of the human serine protease plasmin that retains its enzymatic properties. It is a small molecule designed specifically for use in the eye and is believed to primarily target the fibronectin, laminin and type IV collagen fibers that adhere the vitreous to the retina.

The priority review submission, which is now being prepared, will include data from two pivotal phase 3 trials microplasmin involving 652 patients in the US and Europe.

In October 2011, the European Medicines Agency accepted for review Thrombo Genics’ Marketing Authorisation Application for ocriplasmin for the same indication.

“We are pleased that the FDA has indicated that ocriplasmin meets its criteria for priority review,” said Patrik De Haes, MD, ThromboGenics’ CEO. “This reflects our view that ocriplasmin could represent an important advance in the treatment of symptomatic VMA, including macular hole. We remain on track to meet our timelines for making ocriplasmin available to the many patients suffering from this sight-threatening disorder.”

Symptomatic VMA including macular hole is a progressive condition that if left untreated generally leads to significant visual distortion, deterioration in vision, and in some cases central blindness. Market research conducted by ThromboGenics suggests that there are approximately 500,000 patients annually in the major markets of the EU and the US who could potentially benefit from ocriplasmin.

IN BRIEF
Genentech funds sustained-release Lucentis. Genentech will make its first milestone payment to ForSight Vision4, Inc. as part of an exclusive license agreement to develop the company’s investigational drug delivery device, designed to provide sustained delivery of Lucentis.
Genentech and its parent Roche entered into an agreement with ForSight in December 2010 for exclusive worldwide rights to the company’s proprietary implantable ocular device in the development and commercialization of anti-VEGF-A targeted ophthalmic therapies. This first undisclosed milestone payment is based on Genentech’s decision to submit an Investigational New Drug application for clinical testing of the device in combination with Lucentis.
“The ForSight Vision4 technology has the potential to revolutionize the way we treat ophthalmic disease,” said Eugene de Juan, Jr., MD, founder of ForSight. “Genentech is an ideal partner given their long-term clinical experience with Lucentis and pioneering work in the anti-VEGF therapeutic space.”
The ForSight device is a refillable drug port delivery system designed to release Lucentis over a period of months.

Valeant acquires Eyetech. Valeant Pharmaceuticals has agreed to acquire Eyetech Inc., a privately owned ophthalmic biotechnology company dedicated to the treatment of retina disease, for an upfront payment and potential future milestones. Eyetech currently markets Macugen, the first approved drug therapy for wet AMD. The transaction is expected to be immediately accretive.

Stem cell study for dry AMD. StemCells, Inc. said the FDA has authorized the initiation of a phase 1/2 clinical trial of the company’s proprietary HuCNS-SC product candidate (purified human neural stem cells) in dry AMD. There are no currently approved treatments for dry AMD. The trial will be an open-label, dose-escalation study, and is expected to enroll a total of 16 patients.

Investigators trace endophthalmitis cases to a compounding pharmacy. Unused syringes filled with Avastin and destined for injection into the eyes of wet AMD patients provided investigators with compelling evidence that 12 cases of endophthalmitis reported last summer originated from a single south Florida compounding pharmacy.
A report on the retrospective review of the incidents was published in the February issue of the American Journal of Ophthalmology.
All 12 cases occurred between July 5 and July 8, 2011 at four different medical facilities in south Florida. All patients received Avastin prepared by the same compounding pharmacy. Microbiology cultures for 10 of the affected patients were positive for Streptococcus mitis/oralis. Investigators also found that seven unused syringes prepared by the compounding pharmacy at the same time of the outbreak were also positive for S. mitis/oralis.
After four months of follow-up, all but one patient had count fingers or worse visual acuity and three required evisceration or enucleation.

Clearside has new drug-delivery system. Ophthalmic startup Clearside Biomedical and Hatteras Venture Partners have launched the company with $4 million in venture financing to fund the initial development and clinical testing of Clearside’s ocular microinjection platform for macular edema and retinal vein occlusion.
Clearside’s proprietary ocular microinjection platform has been designed to non-surgically deliver drugs to the suprachoroidal space, which the company says allows a novel way of dosing of therapeutics to the tissues of the posterior segment of the eye and retina.

Iluvien implant moves ahead in European approval process. Alimera Sciences said its Iluvien sustained-release implant for the treatment of DME has received overall approval from a European regulatory body and now goes to seven individual country authorities for final approval. RP


Retinal Physician, Volume: 9 , Issue: March 2012, page(s): 8 - 17