IMT Study Shows Vision Gains
Device Could Help End-stage AMD Patients.
VisionCare Ophthalmic Technologies, Inc., a developer of advanced visual prosthetic devices for the treatment of AMD, announced positive results from the phase 2/3 clinical trial of the investigational Implantable Miniature Telescope (IMT). The data were published in a recent issue of Ophthalmology.
The IMT is currently in the regulatory review process, having received a setback in July when the FDA Ophthalmic Devices Advisory Panel voted 10 to 3 to reject the device because of safety concerns. The IMT is implanted in a complex anterior segment procedure that requires the participation of an anterior segment surgeon, retina specialist, and low-vision specialist for comprehensive patient management.
The Ophthalmology article, entitled "Implantable miniature telescope for the treatment of visual acuity loss resulting from end-stage age-related macular degeneration," details the results from the IMT002 trial that enrolled 217 patients at 28 U.S. investigational sites. Patients entering the trial had severe vision loss due to the characteristic central blind spot caused by end-stage macular degeneration. The publication reports 90% of patients met or exceeded the protocol-specified primary efficacy endpoint of visual improvement, defined as a 2-line gain in either distance or near vision on the study eye chart. The protocol stated the endpoint would be achieved if at least 50% of patients met this target.
"This is truly a breakthrough because it is the first clinical trial to show the potential for improved vision and quality of life specifically in patients with bilateral, irreversible AMD," said Henry L. Hudson, MD, lead author of the IMT002 study publication and retina specialist at Retina Centers, PC, in Tucson, Ariz. "From an efficacy standpoint, we hoped that half of this study population with untreatable forms of AMD could achieve at least a 2-line visual acuity gain. The results surpassed our expectations because 90% achieved the efficacy endpoint, and, furthermore, over two-thirds of patients improved by at least 3 lines and one-quarter improved by at least 5 lines in distance vision."
Secondary efficacy outcome measures suggest improvement in patients' vision-related quality of life and activities of daily living. On the National Eye Institute 25-item Visual Function Questionnaire, patients improved significantly from baseline in 7 of 8 relevant vision-specific and psychosocial subscales, including General Vision, Social Functioning, and Dependency. However, corneal endothelial cell density, a safety endpoint, was reduced 20% from preoperative at 3 months and 25% at 1 year, compared with the 17% protocol-specified target.
"In an end-stage AMD population, the indicated improvements in this study are substantial compared to risks of surgery," commented R. Doyle Stulting, MD, PhD, professor of ophthalmology at Emory University in Atlanta and study coauthor.
"Despite the endothelial cell loss
from surgery, we believe that corneal health was maintained," said Stephen S. Lane,
MD, the trial's medical monitor and adjunct professor of ophthalmology, University
of Minnesota. "There was a significant correlation between postoperative cell loss
and the level of corneal edema on the first postoperative day. Therefore, it appears
that the majority of cell loss was due to the impact of the surgical procedure.
Stabilization of cell density 3 to
12 months after surgery was consistent with what we'd expect after large-incision intraocular surgery.
"While the techniques required to implant the device are well within the skill set of anterior segment surgeons, a surgeon training program will be utilized to address the risk of acute endothelial cell density loss during implant," Dr. Lane concluded.
On page S-7 of the November/
December issue of Retinal Physician, part of a continuing medical education section titled "Management of vitreous hemorrhage in the high-risk, nonsurgical patient," a quote by Michael A. Singer, MD, was accompanied by a photograph of Kent W. Small, MD. We regret this error and apologize for any confusion.
Seeks to Exit Eye Care
Macugen Sales Continue in Steep Decline.
When OSI Pharmaceuticals announced its intention to acquire Eyetech in a $650 million deal in the summer of 2005, the reaction of the stock market was immediate and sharply negative. Within a matter of weeks, OSI shares fell almost 50% before recovering somewhat.
While OSI saw significant potential in Eyetech's Macugen therapy for wet AMD, the market was clearly dubious about the drug's long-term prospects. What concerned investors was the looming presence of Lucentis, a Genentech treatment for wet AMD, then in phase 3 clinical trials, that had proven far more efficacious than Macugen in studies. While Macugen was a safe drug able to slow, or sometimes even halt, the progression of the disease, Lucentis demonstrated that it could actually improve vision.
As it became clear that Lucentis was likely to be approved and be a formidable competitor, OSI CEO Colin Goddard, PhD, put forward several strategies designed to spur Macugen sales. He advocated the drug as part of a "1-2 punch" in treating AMD, with Macugen serving as a maintenance therapy after initial treatment with the Genentech drug. He also emphasized Macugen's excellent safety profile and its effectiveness when used in the early stages of wet AMD.
Some studies have confirmed that these approaches have validity. However, OSI's advocacy of these strategies proved to be unable to overcome the efficacy obstacle.
Lucentis was approved by the FDA in June 2006 and generated an impressive $153 million in sales in its first 3 months of US availability. Meanwhile, Macugen US sales slumped to just $9 million for the same 3-month period after having recorded sales of $50.5 million in the first quarter of 2006 and $36.7 million in the second quarter.
These plummeting numbers were too compelling for OSI management to ignore.
In November, OSI announced that it planned to exit its eye disease business and would seek to maximize value for Macugen and its research assets through either licensing, partnering, or an outright sale of the business.
"We continue to believe that Macugen's product profile, our induction/maintenance strategy, and promising data in the diabetic retinopathy area will ultimately result in a meaningful place for Macugen in treating retinal eye disease. However, it is evident that a key strategic goal behind our acquisition of Eyetech that of generating positive cash-flow from the eye business in the 2006-2008 period will not be realized," stated Dr. Goddard. "This, and our reluctance to invest near-term in the eye disease business given our priorities in the oncology and diabetes areas, has led us to conclude that we can better realize value from these assets through strategic partnering strategies. In the near-term we, and our marketing partner, Pfizer, intend to continue to support the brand commercially."
OSI said it will continue its important phase 4 LEVEL study designed to test Macugen's effectiveness as a maintenance therapy. The company also plans to continue studies using Macugen to treat diabetic macular edema, diabetic retinopathy, and central retinal vein occlusion. The company believes that impressive results from any or all of these studies could help maximize the value of Macugen in a sale, partnership, or license agreement.
Dr. Goddard asserted that there was already strong interest in the Macugen franchise and that a favorable deal could be concluded in the next 6 to 9 months.
Cellgate begins drug study. Cellgate Inc., a company developing anti-proliferative drugs to combat eye disease, has dosed the first patient in a phase 1 dose-escalation study of CGC-11047 in patients with wet AMD. CGC-11047 is a polyamine analogue that targets hyper-proliferating blood vessel growth.
The open label phase 1 trial is designed to determine the safety and tolerability of CGC-11047. A total of 15 patients will be treated in cohorts of escalating doses. Patients will be treated subconjunctivally, avoiding the need to inject into the eye. Patients will be monitored for adverse events and for preliminary evidence of suppression and regression of choroidal neovascularization following administration.
Merck to purchase Sirna. Pharmaceutical giant Merck has agreed to acquire Sirna Therapeutics, Inc., a developer of a new class of medicines based on RNA interference (RNAi) technology. One of the key target areas of Sirna research is ophthalmic diseases.
RNAi-based therapeutics selectively catalyze the destruction of the RNA transcribed from an individual gene. This enables a novel approach to discovering drugs with the potential to produce highly specific, potent, and long-lasting effects.
Sirna's lead clinical development candidate, Sirna-027, is a chemically optimized, short interfering RNA (siRNA) currently moving into phase 2 development for the treatment of wet AMD as part of a broad collaboration with Allergan, Inc., in the area of ophthalmic diseases.
Combination AMD trial. Novartis Pharmaceuticals said it will conduct a randomized, controlled, multi-center, clinical trial in the United States and Canada to explore combination therapy in the treatment of patients with the wet form of AMD. The DENALI trial will compare the efficacy, safety, and impact on retreatment rates of Visudyne used with Lucentis vs Lucentis monotherapy in patients with subfoveal choroidal neovascularization secondary to wet AMD. Novartis has a partnership stake in Visudyne and is also the international marketer of Lucentis.
The 2-year, 300-patient study will evaluate whether patients treated with combination therapy need fewer treatments than those receiving Lucentis monotherapy.
Eye drops for AMD. Athenagen, Inc., a privately held biopharmaceutical company based in South San Francisco, Calif, said it has begun testing ATG003, its topical therapy for wet AMD, in a phase 1 clinical trial.
ATG003 is a proprietary topical formulation of mecamylamine that has shown efficacy in animal models. Athenagen believes it is a possible alternative to current therapies for AMD that require frequent needle injections directly in the eye. This study represents the first human study of an eye drop antiangiogenic therapy for AMD, with a phase 2 efficacy study expected to follow early next year.
Athenagen says ATG003 is a novel antiangiogenic agent that inhibits endothelial nicotinic acetylcholine (nACh) receptors and has been shown to decrease new blood vessel growth as well as vascular permeability, 2 well-known hallmarks of neovascular AMD. Athenagen's study is a randomized, placebo-controlled, ascending dose clinical trial designed to evaluate ocular tolerability and safety for up to 14 days
Treating Diabetic Retinopathy in Developing Countries
A Retina Clinic in Zimbabwe.
JESSE MAKI & KIMBALL WOODWARD, MD, PHD, FACS
Zimbabwe is a country of amazing natural beauty, from the Masasa-covered mountains to the red earth of the Zambezi valley. Unfortunately, an increasing number of its citizens cannot see this beauty, nor in many cases can they work, care for themselves, or lead productive lives due to visual complications from diabetes.
A general paucity of medical care and the lack of trained specialists, especially in rural areas, contribute to delays in diagnosing diabetes and poor blood glucose control once the disease is diagnosed. In addition, a myriad of social issues that affect the delivery of medical care, including the provision of proper ophthalmic care to individuals with diabetes, have led to an increase in the prevalence of proliferative diabetic retinopathy (PDR) in Zimbabwe. This article chronicles the difficulties in treating diabetic retinopathy in developing countries, specifically in Harare, Zimbabwe, where Kimball (Kim) Woodward, MD, has held an annual retina clinic for the past 9 years in association with Surgical Eye Expeditions (SEE) International and Eyes for Africa.
DIABETES: A GLOBAL EPIDEMIC
The World Health Organization (WHO) estimates that by 2030 the global burden of diabetes will double; one of the regions with the greatest expected increase in prevalence is sub-Saharan Africa.1 A dramatic example of this is found in Zimbabwe, where diabetes has been on the rise since the country declared its independence in 1980.
Previously, diabetes had been a disease more common in the wealthier Caucasian and South Asian populations, but many successful young Africans now enjoy western diets. This change in lifestyle has contributed to a predicted 160% increase in the prevalence of type 2 diabetes mellitus over the next 25 years.
A second factor in the spreading diabetes epidemic within Zimbabwe are current drug shortages in the country, which hinder appropriate care, thus increasing diabetic comorbidities. For example, a lack of antihypertensives limit pharmacologic interventions to control blood pressure. Studies have shown early treatment of hypertension to be as important as controlling glycemic index in minimizing the progression of diabetes.2 In the 1980s, improved accessibility to primary health care and adequate medications protected many Zimbabweans from diabetic complications. However, due to deterioration in the economic and social fabric of Zimbabwe, these same patients, as well as those newly diagnosed with diabetes, no longer have access to resources necessary to control their disease. Consequently, Zimbabwe has experienced drastic increases in diabetic complications, such as cardiovascular disease, nephropathy, and retinopathy.
A CASE IN THE CLINIC
A worn, tired, brightly garbed woman named Tsitsi approached the retina clinic at the Greenwood Park Eye Center in Harare. Tsitsi had heard of the clinic that provided free care. She walked for over half a day to have her 13-year-old son see the doctor. Mother and son waited patiently until the doctor was able to see them. Tsitsi's son had been blind in 1 eye from birth, and it was quickly apparent that we could offer no help to her son, who had permanent damage, likely from congenitally acquired toxoplasmosis. It was also clear from Tsitsi's mannerisms and the way she squinted at the admission forms, that her vision was not quite intact.
Her blood pressure was taken in the office and found to be 140/90. A finger-stick glucose was 238. She told the doctors that she had pills for her "blood" but had not taken them in years and had not seen a doctor in equally as long. She lived hours outside of Harare, the closest city, and lacked money for medications. Indirect examination of Tsitsi's eyes showed evidence of diffuse neovascularization and hemorrhaging consistent with proliferative retinopathy. She was unaware of her medical condition, nor did she know that it was contributing to her deteriorating vision.
That afternoon, Tsitsi underwent vitrectomy and photocoagulation. At follow-up the next day, the patient thanked the doctors profusely. While disappointed that the doctors could not save her son's vision, she was grateful for the gift they had given her. Maintaining her vision would allow her to continue working and support her family.
She told the team that paying for her operation would have forced her to make significant sacrifices. She would not be able to pay the school fees for her son and other children. She was worried that tears would hurt her recently repaired eye, but those worries could not keep her eyes from welling up as she communicated her heartfelt gratitude to the doctors at the Greenwood Park Eye Center.
LITTLE ACCESS TO MEDICAL CARE
The obstacles Tsitsi faced to attain care are not rare; rather they are the norm in Zimbabwe. The majority of patients live in rural areas and survive through subsistence farming or hold poorly paying jobs as laborers. They lack transport to urban-based medical facilities and pharmacies, do not have the financial means to pay for care, and are often unaware of the complications of their diagnosis. Access to affordable care and transport to medical facilities are 2 of the most pressing and potentially remediable barriers to preventing diabetic comorbidites.
Of the 22 certified ophthalmologists in Zimbabwe, 13 are in Harare, the capital city, and serve the 1.2 million residents there. Zimbabwe has a total population of 12 million, 60% of whom are rural citizens. There are 3 ophthalmologists in the country who perform vitrectomies and 5 laser centers in the large cities of Harare and Bulawayo. The effects of concentrating ophthalmologists and modern equipment in only a few urban areas are compounded by a severe fuel shortage in Zimbabwe that has hindered transportation in all areas of the country. It is common for people to wait in line for days to get fuel, often leaving cars in line overnight.
These limitations challenge the ability of patients with diabetes in Zimbabwe to follow recommendations for annual dilated eye exams. Routine exams are critical for timely diagnosis and treatment of proliferative diabetic retinopathy with panretinal laser treatments. There is a limited window of opportunity to treat PDR. Panretinal photocoagulation (PRP) must be offered to patients on a regular basis in order to slow continued retinal damage from PDR and prevent more serious complications such as vitreous hemorrhage, retinal detachment, and blindness.
Unfortunately, obtaining regular retinal exams can prove highly difficult for patients in Zimbabwe, especially those in rural areas. Financial difficulties, a poor patient-to-provider ratio, and the scarcity of highly skilled specialists are barriers to medical care. Overall, these hurdles have led to a marked decrease in non-emergency medical visits and have prevented even those patients with the time and financial means from receiving adequate care.
Further complicating the delivery of adequate care to diabetics are barriers that hamper clinic operations. To perform PRP, for example, clinics must obtain an endolaser and train local ophthalmologists. Unfortunately, the cost involved in the purchase and maintenance of an endolaser is far from insignificant, especially for clinics already struggling to provide care under the constraints of too few skilled physicians, drug shortages, and other financial burdens. Patients with evolving PDR also need to be properly diagnosed by regular fundoscopic exam. In developed nations, use of a flourescein angiogram would be advised to measure the extent of neovascularization after retinopathy is detected, but this test is rarely performed in Zimbabwe, even in the best clinics. The Greenwood Park Eye Center, the leading eyecare center in Zimbabwe, performs approximately 1 angiogram every 1 to 2 weeks.
WORKING FOR CHANGE
Because changing the social structure to improve medical care in Zimbabwe would require local political action, a more practical method to improve care is to augment the training and skills of local ophthalmologists. This process is enhanced through the donation of supplies and equipment that improve the daily functionality of eye clinics. For the past 17 years, Dr. Woodward has been doing this by teaming with SEE International, a Goleta, Calif-based nonprofit organization dedicated to providing medical, surgical, and educational services to the disadvantaged blind worldwide, and Eyes for Africa, a Zimbabwean organization devoted to serving the vision needs of the rural poor. Dr. Woodward visits Harare for 1 week each year to train local ophthalmologists in diagnosis, treatment, and surgical skills. He operates side-by-side with local ophthalmologists and brings vital donated supplies. The efforts of Dr. Woodward, SEE International, and Eyes for Africa provide sustainable improvements to the care of patients who have PDR.
Prior to treatment at a retina clinic sponsored by SEE and Eyes for Africa, 2 local Zimbabwean ophthalmologists, Drs. Guramuntunhu and Sibanda, assess patients with severe or complicated retinal cases. Patients with treatable conditions are seen during the clinic week. A typical day in the clinic consists of a morning educational lecture by Dr. Woodward for local doctors, followed by patient consultations between the doctors. Those patients who are referred for surgery undergo afternoon operations, often on the same or the next day.
The lectures focus on the detection and treatment of diabetic retinopathy and include slides and surgical videos. Age-related macular degeneration, vitrioschisis, and anterior hyaloidal proliferation are among other topics discussed. These topics are then applied in the consultations and the surgeries. Dr. Woodward guides the local physicians through the cases so that they are equipped with the skills necessary to handle similar cases in the future. Many medical missions rely on the skills of foreign surgeons. These missions can often address a large number of cases in a short period of time. However, with the departure of these foreign doctors, so too goes the skill. Thus, education of local physicians is important to improve overall quality of retinal care in Harare in a long-term, sustainable, manner.
A new addition to retinal surgery in Harare this year is the use of triamcinolone acetonide during vitrectomy surgery. Dr. Guramuntunhu has been pleased with the results and reported increased confidence while extracting posterior membranes. The anti-inflammatory effects of triamcinolone are expected to be as beneficial to surgeons in Zimbabwe as they have been in the United States.3,4 Given the extent of the ophthalmic burden of diabetic disease in Zimbabwe, improvements in treatment will no doubt have far reaching effects.
KEY TO SUCCESS: TRAINING LOCAL DOCTORS
The take-home message from the clinic in Zimbabwe is clear: there is an urgent need to provide access to ophthalmic care for patient with type 2 diabetes mellitus. PDR does not resolve without interventional measures; however, with laser treatment the risk of vision loss decreases to less than 5%. Thus, when patients are not seen regularly by a primary-care physician, much less by an ophthalmologist, untreated ophthalmic complications secondary to diabetes are common. By increasing the early detection of PDR, patients can be treated aggressively to preserve their vision and quality of life. This is an effort that cannot be accomplished 1 week each year by 1 doctor; it needs the dedication and understanding of local ophthalmologists who treat the people of Zimbabwe year-round. With this greater goal in mind, Dr. Woodward has been offering his skills and services to the patients and doctors in Harare, Zimbabwe, for the last decade and can be undoubtedly credited with improving the quality of care for retinal patients throughout Zimbabwe.
|Jesse Maki is a third-year student at Harvard Medical School in Boston and can be reached at firstname.lastname@example.org. Kimball Woodward, MD, PhD, FACS, is owner of Orangetown Ophthalmology, LLC in West Nyack, NY. Neither author has any financial interest in the information contained within the article.|
1. The World Health Organization. Diabetic Care page. Available at http://www.who.int/diabetes/facts/en/diabcare0504.pdf. Accessed October 12, 2006.
2. Scheen AJ. Prevention of type 2 diabetes mellitus through inhibition of the Renin-Angiotensin system. Drugs. 2004;64:2537-2565.
3. Jonas JB. Intravitreal triamcinolone acetonide: a change in paradigm. Ophthalmic Res. 2006; 38:218-245.
4. Bandello F, Polito A, Pognuz DR, Monaco P, Dimastrogiovanni A, Paissios J. Triamcinolone as adjunctive treatment to laser panretinal photocoagulation for proliferative diabetic retinopathy. Arch Ophthalmol. 2006;124:643-650.