What's hot in ophthalmic development?

For a change, the posterior segment is the focus of several of this year’s advances in ophthalmology.

In recent years, refractive surgery has dominated the news of new products and developments in the pipeline. But this year glaucoma and vitreoretinal technology have been responsible for a good bit of the ophthalmic industry buzz. Two glaucoma products from InSite Vision and a retina product from Ista Pharmaceuticals have been among the most interesting developments to date in 2002.

Optineurin

The biggest news in glaucoma research so far this year has been the report by InSite Vision and the University of Connecticut Health Center regarding the discovery of the gene optineurin, which has been linked to primary open-angle glaucoma.

InSite and the university announced the discovery of the optineurin gene and its mutations, which have been reported to cause POAG and normal-tension glaucoma (NTG). The optineurin gene and its mutations were discovered through an international collaborative research study led by Mansoor Sarfarazi, PhD, professor of human genetics and director of the Molecular Ophthalmic Genetics Laboratory, Surgical Research Center at the University of Connecticut Health Center. The University of Connecticut has filed for patent protection of the optineurin gene and its mutations.

For its part, InSite announced the licensing of exclusive, worldwide rights to the optineurin gene and its mutations from the university. Under the licensing agreement, the university will receive from InSite Vision a licensing fee, a milestone payment and royalties from the sale of products incorporating the technology.

According to a research paper by Dr. Sarfarazi, published in Science, 54 families with adult-onset POAG and 124 sporadic POAG patients, the majority of whom are NTG patients, were studied. Dr. Sarfarazi and colleagues identified optineurin, the POAG causative gene, on chromosome 10p14 and determined that mutations in optineurin may be responsible for 16.7% of hereditary forms of NTG glaucoma with an additional risk factor of 13.6% in both familial and sporadic cases.

“This is a major breakthrough in glaucoma research and diagnosis,” said study clinician Robert Ritch, MD, of New York. “Traditionally, elevated intraocular pressure has been a key factor in identifying potential glaucoma patients. However, NTG patients, who comprise up to 30% of POAG patients in the United States and 70% of POAG patients in Japan, have been difficult to screen and detect because of a lack of intraocular pressure elevation. This population represents the majority of undiagnosed glaucoma patients. The discovery of optineurin and its mutations should enable us to identify potential NTG patients and provide them with early treatment and improve the disease outcome.”

Said S. Kumar Chandrasekaran, PhD, InSite Vision’s chief executive officer, “With a licensing agreement for Optineurin and its mutations in place, InSite Vision currently expects to begin developing a genetic test that may be able to identify individuals with opti neurin mutations before permanent visual damage occurs. Detection is important because appropriate treatment may slow the progress of glaucoma and allow patients to lead more normal lives for a longer period of time.”

OcuGene

OcuGene, also from InSite Vision, is a diagnostic/prognostic technology de signed to identify multiple glaucoma genetic markers from a single sample obtained through a cheek brush. This test identifies patients who could have a severe form of POAG and those with a hereditary disposition to the disease.

InSite, along with academic collaborators the University of California-San Francisco and the University of Connecticut Health Center, have identified genetic markers associated with juvenile glaucoma, primary congenital glaucoma and POAG, the most prevalent form of the disease in adults.

OcuGene is expected to provide physicians with an additional tool for the management of their patients with glaucoma. It will benefit patients by making it possible for them to receive individualized treatment based on their genetic makeup.

The test provides information on the role of the trabecular meshwork inducible glucocorticoid response (TIGR) gene in POAG.

OcuGene is designed to detect a genetic marker (mt-1) in the promoter region of the glaucoma-related TIGR gene for patients with POAG.

The test’s developer said OcuGene can also screen for the presence of a number of mutations in the coding region of the TIGR gene in high-risk persons such as relatives of patients with glaucoma and ocular hypertension and those who are suspected of having glaucoma.

The OcuGene test can detect changes in two regions of the TIGR/MYOC gene, the promoter and coding regions.

If a glaucoma patient tests positive for the promoter region (mt-1) marker, the patient may have a more aggressive form of POAG. The increased aggressiveness of the disease can take the form of less response to IOP-lowering drugs and/or greater visual field deterioration.

A positive OcuGene test result for the promoter (mt-1) region of the TIGR/ MYOC gene can be interpreted as a signal that patients have a more severe form of glaucoma resulting in greater glaucomatous loss, and also reduced response to some IOP-lowering drug treatments.

If an individual tests positive for a coding region mutation, the company says a significant possibility exists that the individual will develop glaucoma. Relatives of patients with glaucoma and ocular hypertension and those who are suspected of having glaucoma can be genotyped for these mutations, and if the results are positive the ophthalmologist can follow up with them for the presence of glaucoma.

InSite Vision describes the OcuGene test as complementary to current diagnostic tests, including tonometry and visual field determinations. They suggest more frequent eye exams could be considered for patients whose OcuGene results are positive.

Not everyone is enthusiastic about the prospects for OcuGene.

Wallace Alward, MD, discussed genetic testing for the TIGR/MYOC gene at the 2002 American Glaucoma Society (AGS) annual meeting in San Juan, Puerto Rico. Dr. Alward said he was disappointed with the narrow focus of the OcuGene test. He said OcuGene tests only for three of the 34 known mutations associated with glaucoma and that those three are not even among the most common mutations.

Dr. Alward said he believes OcuGene is not cost-effective because it would have missed all 13 mutations he found in his own study of 393 POAG patients. Dr. Alward’s study screened the entire coding sequence of the TIGR gene for mutations.

“In fact, we found two mutations that have not been previously described in the literature,” he said.

Dr. Alward said that of the two parts to the OcuGene test, “one part screens for these three coding-sequence mutations. These three mutations are rare, and a negative result would be meaningless. A positive result would occur less than 0.25% of the time. This is not cost-effective at any price, especially not at $200,” he noted.

“The other part is the screen for the MYOC (mt-1) promoter polymorphism that was described in a paper by Dr. Columb to represent a marker for resistance to glaucoma treatment,” Dr. Alward said. “In reviewing that paper, I felt the conclusion was flawed. In our examination of a much larger series of consecutive glaucoma patients, the MYOC (mt-1) promoter polymorphism had no relationship to disease severity.”

Dr. Alward said he would not use the test, but he noted that there are no other tests on the market today. He said he is hopeful that there will someday be a test for a large number of glaucoma genes, once they are identified.

“That test would need to be sensitive, specific and inexpensive,” he said.

In the discussion following Dr. Al ward’s presentation at the AGS meeting, Jon R. Polansky, MD, pointed out that the effects of the mt-1 test do not become apparent in many patients for more than 10 to 15 years of follow-up. Dr. Polansky, of the University of California–San Francisco, said this time-frame was likely to be beyond the period evaluated by Dr. Alward.

Vitrase

Ista Pharmaceuticals announced in early January the results of a pilot phase 2a study of Vitrase, a drug being developed for the treatment of patients with diabetic retinopathy.

Sixty patients in Mexico who were diagnosed with nonproliferative diabetic retinopathy were enrolled in the prospective, randomized, placebo-controlled study. The study’s primary purpose was to evaluate the safety and efficacy of Vitrase in inducing a posterior vitreous detachment (PVD). Ista officials said they believe the PVD may be beneficial in the early treatment of diabetic retinopathy by delaying the progression of the disease. A secondary endpoint was the determination of Vitrase’s impact on slowing the progression of diabetic retinopathy over a 1-year period.

Interim study results at 16 weeks post-treatment, presented at the 2001 American Academy of Ophthalmology meeting, demonstrated that complete PVDs were documented in 60% of eyes treated with a single dose of Vitrase. This is compared with only 6% of patients in a control group that received saline injection. In the study’s two additional treatment groups, complete PVDs were documented in 53% of eyes treated with sulfur-hexafluoride (SF6) gas and in 50% of eyes treated with a combination of Vitrase and SF6 gas.

In order to assess and measure the progression of diabetic retinopathy for study patients, seven field fundus photographs were taken at approximately 16 weeks following study entry and 12 months later. The fundus photographs were reviewed in a masked fashion by an independent reading center to determine a score on the Early Treatment of Diabetic Retinopathy Study (ETDRS) retinopathy severity scale. The ETDRS scores were evaluated to identify any changes in the patients’ diabetic retinopathy over the 1-year evaluation period. Of the study’s 60 patients, complete sets of fundus photographs were available, analyzed and scored for 46 patients.

Although the study was not designed to demonstrate statistical significance for progression of diabetic retinopathy among study groups, evaluation of the ETDRS scores did highlight encouraging trends for slowing the progress of diabetic retinopathy. Of the 46 patients with fundus photographs that were analyzed and scored, 67% of patients treated with Vitrase had stable ETDRS scores, indicating no measurable progression of diabetic retinopathy at 1 year. This compares to stable ETDRS scores for 38% of patients treated with saline, 40% of patients treated with SF6 and 43% of patients treated with Vitrase plus SF6.

Worsening of ETDRS scores, indicating a progression of diabetic retinopathy, was seen in 13% of patients treated with Vitrase, 38% of patients treated with saline, 20% of patients treated with SF6 and 21% of patients treated with Vitrase plus SF6.

Patients were also assessed to determine whether the occurrence of a PVD on or before week 16 had any effect on the progression of diabetic retinopathy throughout the 1-year follow-up. For patients who had a complete PVD by week 16, 50% treated with Vitrase had stable ETDRS scores throughout the 1-year period, as compared to none of those treated with saline, 30% of those treated with SF6 and 40% of those treated with Vitrase plus SF6.

Adverse events were similar in type and frequency across all groups, with reduced visual acuity the most frequently noted adverse event.

“The study results suggest that Vitrase induced a physiological change that may be beneficial to the eye,” stated Baruch Kuppermann, MD, one of the principal investigators of Vitrase. “Although this pilot study was not designed to demonstrate statistical evidence of efficacy in delaying the progression of diabetic retinopathy among study groups, the results support further clinical study to evaluate a potential role for Vitrase in the early treatment of diabetic retinopathy.”

In early March, Ista announced it had begun the process of unmasking data and initiating the analysis of its phase 3 studies of Vitrase for the treatment of severe vitreous hemorrhage. The company’s analysis will examine both the primary surrogate endpoint (vitreous hemorrhage clearing) and other clinically relevant parameters.

Until now, the data have not been seen or reviewed by executives at Ista or representatives of the Food and Drug Administration.

“We have taken into consideration the FDA’s comments in making adjustments to our statistical analysis plan and submitted the changes to the FDA. In addition, we intend to provide the agency with a complete validation protocol for our surrogate endpoint prior to submission of the new drug application,” said Vicente Anido Jr., PhD, Ista’s chief executive officer. “We will now begin the process of unmasking the data, conducting the statistical analysis and verifying its accuracy. We will report results once they become available.”

For Your Information:

• Wallace Alward, MD, can be reached at the department of ophthalmology of the University of Iowa, 200 Hawkins Drive, Iowa City, IA 52242; (319) 356-3938; fax: (319) 353-7699. Dr. Alward has no direct financial interest in the products mentioned in this article, nor is he a paid consultant for any companies mentioned.
• Jon R. Polansky, MD, can be reached by phone and fax at (415) 388-0389. Dr. Polansky is a consultant to Insite Vision and a coholder of patents relating to the TIGR/MYOC gene through UCSF.
• Baruch Kuppermann, MD, can be reached at UC-Irvine Dept. of Ophthalmology, 118 Med Surge I, Irvine CA, 92697; (949) 824-6256; fax: (949) 824-4015.
• Vicente Anido Jr., PhD, CEO of Ista Pharmaceuticals, developer of Vitrase, can be reached at 15279 Alton Parkway, Suite 100, Irvine, California 92618; (949) 788-6000; fax: (949) 788-6010.
• Robert Ritch, MD, can be reached at the New York Eye and Ear Infirmary, 310 E. 14th St., New York, NY 10003; (212) 673-5140; fax: (212) 420-8743.
• S. Kumar Chandrasekaran, PhD, chief executive officer of InSite Vision, can be reached at 965 Atlantic Ave., Alameda, CA 94501; (510) 865-8800; fax: (510) 865-5700.

Reference:

• Rezaie T, Child A, et al. Adult-onset primary open-angle glaucoma caused by mutations in optineurin. Science. 2002;295:1077-1079.