With energy prices soaring, most people hear the word pipeline and immediately think of oil. But in health care, the word describes a vital flow of new medications and technologies that allow us to provide better care for our patients.
Nowhere is this more evident than in eye care, which in the past decade has seen the emergence of new topical antibiotics, glaucoma medications and procedures, and treatments for age-related macular degeneration. This article addresses some of the promising new treatments and technologies that are approaching FDA approval and that we may be using in the future.
An estimated 2.2 million people in the United States are affected by glaucoma. In the past decade, the advent of new technology to detect, diagnose and manage glaucoma has been paralleled by the introduction of multiple medications, and several more are under development or in FDA trials.
Santen Pharmaceutical Co. Ltd. reported preliminary results of overseas clinical trials of two drug candidates for use in treating glaucoma and ocular hypertension:
DE-092 (INN: Olmesartan), is an angiotensin II receptor antagonist that is currently available to treat high blood pressure. DE-092 blocks the action of a substance in the body that causes blood vessels to tighten, thus relaxing the vessels. Increased blood flow would theoretically be a positive development in the treatment of some glaucoma patients.
In the early Phase II clinical study in the United States, DE-092 reduced IOP. However, efficacy was insufficient, and investigators observed no clear dose-response relationship.
DE-085 (INN: Tafluprost), a prostaglandin derivative. A European Phase III trial compared DE-085 to Xalatan (latanoprost 0.005%, Pfizer). Results demonstrated a strong IOP-lowering effect, but DE-085 did not demonstrate inferiority to latanoprost. After completion of a current study comparing DE-085 with Timoptic (timolol maleate 0.5%, Merck), Santen plans to review the development plan for DE-085 in the United States and Europe.
Alcon Laboratories recently announced that the Committee for Medicinal Products for Human Use (CHMP) has adopted a positive opinion on the initial marketing authorization for DuoTrav solution (travoprost 0.004%/timolol 0.5%). One daily drop of DuoTrav lowers IOP via two mechanisms: timolol, a beta-blocker, which decreases aqueous humor production, and travoprost, a prostaglandin analogue, which increases uveoscleral outflow. Approximately one-half of all glaucoma patients currently take multiple medications for their condition. Inclusion of both types of drugs in one medication increases convenience (and possibly compliance) for patients who require multiple glaucoma medications.
In 2004, Inspire Pharmaceuticals Inc. agreed to license exclusively several patents from the Wisconsin Alumni Research Foundation for use in developing new therapeutics for treating glaucoma. Dr. Paul Kaufman, professor and chair of the Department of Ophthalmology and Visual Sciences at the University of Wisconsin-Madison, and Dr. Benjamin Geiger, professor of molecular cell and tumor biology and dean of biology at the Weizmann Institute of Science in Israel, conducted extensive research on cytoskeleton-targeting drugs as potential glaucoma therapies.
Their research has focused on inhibitors of actomyosin contractility or actin microfilament assembly. These classes of drugs can relax and alter cell and tissue shape within the trabecular meshworkthe primary site of resistance to outflow. Increased resistance, a common finding in patients who have primary open-angle glaucoma (POAG), may lead to elevated IOP and the optic neuropathy associated with glaucoma.
Biovitrum AB, a pharmaceutical manufacturer based in Sweden, has initiated Phase I trials for its glaucoma drug candidate: BVT.28949. This specific and selective 5HT2a-receptor antagonist increases aqueous humor outflow. Biovitrum claims that BVT.28949 has shown neuroprotective potential as well. The initial target for the drug is the treatment of POAG, but researchers believe it will also prove useful in managing normal-tension glaucoma.
Allergan Inc. is currently seeking approval of memantine, which is available overseas for treating Parkinsons disease and other neurodegenerative disorders. Memantine may also help prevent retinal ganglion cell loss in glaucoma patients. Although the compound is in Phase III clinical trials, it is only in the early stages of a five-year study to demonstrate whether it can prevent visual field loss. With its neuroprotective effects, memantine may have special applications for patients who suffer from normal-tension glaucoma.
In March 2006, the CHMP recommended that the European Commission approve Ganfort, Allergans Lumigan (bimatoprost)/timolol combination solution for the treatment of glaucoma. Ganfort is indicated for the reduction of IOP in patients who have open-angle glaucoma or ocular hypertension and have not achieved target pressures with a topical beta-blocker or prostaglandin analogue. Whether this product obtains approval in the United States remains to be seen.
Beta blockers were once the drug of choice for glaucoma therapy, but they have lost favor partly because of adverse systemic effects, including depressed heart rate, respiratory distress, impotence and depression. OT-730 (Othera Pharmaceuticals Inc.), has a modified beta-blocker structure designed to be stable and effective in the eye but rapidly break down into inert components upon entering the bloodstream. OT-730 potentially could lower IOP as effectively as the best beta-blockers while significantly reducing the risk of systemic adverse effects.
OT-730 potentially could lower IOP as effectively as the best beta-blockers while significantly reducing the risk of systemic adverse effects.
An estimated 90 million Americans suffer from some degree of dry eye. Prescription dry eye drug sales in the United States totaled approximately $200 million in 2005, and they are expected to reach $350 million to $700 million annually within three to five years. Several promising dry eye products are in development.
ISTA Pharmaceuticals Inc. has announced positive preliminary results from a randomized, three-arm (placebo/3.0%/3.9%) Phase IIb clinical study of ecabet sodium, a prescription eyedrop for treating keratoconjunctivitis sicca. Ecabet sodium represents a new class of molecules that increase the quantity and quality of mucin produced by conjunctival goblet cells and the corneal epithelium. Early results favor the lower (3%) concentration in ecabet sodiums ability to treat corneal staining and blink rate. Patients treated with this lower dose reported fewer symptoms, as measured by the Ocular Surface Disease Index.
FDA approval of INS365 Ophthalmic (diquafosol tetrasodium, Inspire Pharmaceutical) has proven to be elusive. The compound is meant to stimulate the release of natural tear components (mucin, lipids and lacrimal fluid). Inspire has completed four Phase III clinical trials using diquafosol to treat dry eye disease. The company received an FDA approvable letter for diquafosol in December 2003. In June 2005, Inspire amended its New Drug Application and received a second FDA approvable letter in December. The company met with the FDA regarding the second approvable letter in March, and it is currently providing the agency with additional information.
Systane Free potentially could be used as a medication carrier; but perhaps more important, it will be useful for future therapy delivery systems that extend beyond dry eye management.
Weve seen an increasing number of cases of exudative (wet) and non-exudative (dry) age-related macular degeneration (AMD) as the U.S. population ages. Wet AMD tends to be a rapid-onset disease and is ultimately more harmful to vision than dry AMD. Patients can benefit from new therapies to treat AMD, but they require injections every four to six weeks. Fortunately, research into new treatments has been increasing.
GenVec Inc., a biopharmaceutical company, recently announced results of a Phase I clinical study of AdPEDF gene therapy. AdPEDF contains the gene for human pigment epithelium-derived factor (PEDF), a protein that regulates blood vessel growth (angiogenesis) in the eye and protects the cells of the retina from damage. Previous animal studies demonstrated that increased PEDF expression in the eye might prevent the angiogenesis that can cause vision loss in AMD patients.
In this study, 28 patients with advanced neovascular AMD each received a single intravitreal injection of AdPEDF. Patients showed evidence of stabilization that lasted six to 12 months after treatment. No serious adverse events, severe ocular inflammation or dose-limiting toxicities were reported.
Alimera Sciences Inc. and pSivida Limited announced in March that an independent Data Safety Monitoring Board recommended the continuation of its Phase III clinical trial of Medidur. The tiny, injectable device is designed to deliver fluocinolone acetonide, a corticosteroid, to the retina for up to three years, for treatment of diabetic macular edema (DME), a common complication of diabetic retinopathy and the leading cause of vision loss in people younger than age 65. DME affects an estimated 500,000 people in the United States.
RegenMed, a development-stage biotechnology company, announced in February that its anti-SDF-1 treatment appears to prevent retinal neovascularization and accompanying sequelae, such as fluid and blood leakage, new blood vessel growth, and scar tissue development. SDF-1 is a cytokine that enables cells to transmit signals to one another. Many tissues in the body express SDF-1 in response to an injuryessentially issuing a call for help. SDF-1 recruits blood cells to areas of the body where it is expressed.
Retinal surgeons in the United States perform approximately 200,000 vitrectomies annually. Patients who undergo vitrectomy are likely to develop cataracts. Many of these eyes are already fragile, so cataract surgery is risky.
Free radicals are believed to be one of the causative agents in the development of post-vitrectomy cataracts. In November 2005, Othera announced the beginning of a Phase II clinical trial of OT-551, a topical agent developed to prevent or arrest the progression of cataracts in post-vitrectomy patients. The drug is a potent catalytic antioxidant and has already undergone a Phase I safety and comfort study in healthy volunteers. The Phase II study was a double-masked, randomized, placebo-controlled trial lasting 12 months.
In November 2005, Othera announced the beginning of a Phase II clinical trial of OT-551, a topical agent developed to prevent or arrest the progression of cataracts in post-vitrectomy patients. The drug is a potent catalytic antioxidant and has already undergone a Phase I safety and comfort study in healthy volunteers.