Treatments for retinal diseases are expected to overtake those of glaucoma by 2014, “making retinal disease the most lucrative sector of the ophthalmic drugs market, overtaking the glaucoma sector,” according to the report, “Macular Degeneration (AMD) and Diabetic Retinopathy (DR): World Drug Market 2011–2021.”
The age-related macular degeneration (AMD) and diabetic retinopathy segment of that market generated just over $3 billion in 2010. Visiongain projects those revenues to climb to nearly $5.1 billion by 2014. The overall market for ophthalmic therapeutics is expected to reach $18.7 billion this year. Ten-year forecasts for ocular disease therapeutics predict steady growth.
Interest in these diseases is driven by the success of drugs like Genentech’s Lucentis®, which generated $1.5 billion in 2011, as well as an aging population with an increasing prevalence of ocular disorders and increased global demand for innovative therapeutics.
“Back-of-the-eye diseases are the leading cause of blindness in the developed world, but they’re very difficult to treat,” according to Paul Ashton, Ph.D., president and CEO, pSiveda. The challenge is delivering drugs to the back of the eye.
“There have been big advances in wet AMD therapies recently, targeting vascular endothelial growth factor (VEGF),” Dr. Ashton says. Excessive VEGF production causes blood vessels to become fragile, allowing fluids to leak into surrounding tissues where they may damage the macula and create blind spots in central vision.
Standard therapy has been Genentech’s VEGF inhibitors Lucentis (ranibizumab) and the off-label use of Avastin® (bevacizumab). These are equally effective at improving vision, but the improvement only lasts six to eight weeks.
Regeneron, in collaboration with Bayer HealthCare, is challenging these drugs with a similar VEGF inhibitor, Eyela® (aflibercept). Aflibercept is a fusion protein that binds all forms of VEGF and placental growth factor (PlGF), which are involved in the abnormal growth of new blood vessels in ocular and other diseases. It gained FDA approval last November for wet AMD and may be injected every 8 to 10 weeks. This improvement over Lucentis and the slightly lower cost is expected to generate significant savings in healthcare costs. The therapy is in Phase III trials for central retinal vein occlusion and diabetic macular edema.
In another approach, Acucela is in Phase II trials using visual cycle modulators to lighten the metabolic load on the retina by reducing the activity of the rod visual system. This protects the retina from light damage, improves retinal vasculature, and reduces the accumulation of A2E and other retinal-related toxic by-products.
GlaxoSmithKline has two drugs in Phase II trials for ocular therapy: darapladib, an oral Lp-PLA2 inhibitor for diabetic macular edema, and pazopanib (Votrient®), a multi-kinase angiogenesis inhibitor in eye drop form for AMD. Early-stage work also is under way for neovascular AMD, dry AMD, diabetic retinopathy, diabetic macula edema, uveitis, and glaucoma, as well as for technologies for drug delivery.
Eye drops have been a standard delivery mechanism, “but they don’t penetrate to the back of the eye,” Dr. Ashton says. GSK and Sanofi are developing penetrating eye drops. This could have profound implications for glaucoma simply because “people forget to administer eye drops, especially for conditions that aren’t painful. Therefore, physicians never know for certain if the drugs are ineffective or whether the patient is noncompliant,” Dr. Ashton says.
Implants offer another approach. pSivida just developed an implant that can be injected in a physician’s office, using a fine-gauge needle to place an eyelash-sized tube at the back of the eye. The injectable micro-inserts already are approved to treat chronic diabetic macular edema in several European countries.
The micro-inserts release a therapeutic at a consistent rate during 36 months, delivering the compound directly to the eye and thereby avoiding systemic side effects. In the U.S., the first patient was enrolled in June in Phase III trials to study their use in treating posterior uveitis. That condition is the third leading cause of blindness in the U.S., affecting approximately 175,000 people. Other applications also are possible.
Research into the use of porous silicon as a delivery system is a core endeavor at pSivida. As Dr. Ashton explains, “Silicon can be treated so it becomes extremely porous, expanding its surface area so that a 1 cm cube has the surface area of two tennis courts. Treated proteins fit inside the pores and stick to the silicon, preventing them from aggregating.
“We can control the diameter to absorb antibodies or certain therapeutics,” he says. Loading takes 5 to 6 minutes. This delivery mechanism is expected to deliver therapeutics at a consistent rate for 6 months, rather than the 6 to 10 weeks possible with competing technologies.
NeuroTech demonstrated success earlier this year involving NT-501 in a Phase II study for geographic atrophy associated with dry AMD, and in a prospective study for retinitis pigmentosa. NT-501 is an intraocular implant of human cells genetically modified to secrete ciliary neurotrophic factor (CNTF)—a nerve growth factor the company says can rescue and protect dying photoreceptors.
NT-501 continually delivers therapeutics to the back of the eye using NeuroTech’s encapsulated cell therapy, bypassing the blood-retinal barrier, which has been a long-standing obstacle in back-of-the-eye diseases. The technology encapsulates specific protein-producing human cells in a semipermeable hollow fiber membrane that protects the cells from the immune system while allowing oxygen and nutrients to enter. This technology also may be used to deliver other therapeutics, including NT-503, a VEGF inhibitor. Trials for NT-503 are in early stages.
Results are measured noninvasively using a new diagnostic technology, adaptive optics scanning laser ophthalmoscopy, to measure cone photoreceptor cells and their rate of degeneration.
Regenerative therapies are in the early stages of work, most often at small biotech companies that are off analysts’ radar screens. “A lot of small steps are being taken to regenerate tissue and restore vision. Regenerative medicine will have a very positive impact in ophthalmology,” Dr. Ashton says.
A Phase Ib trial by QLT reported a 22% improvement in the visual field of patients with retinitis pigmentosa and Leber congenital amaurosis caused by defects in the RPE65 or LRAT genes. Visual acuity improved for 17% of the patients.
The drug, QLT091001, replaces the 11-cis-retinal retinoid. The company plans to conclude trials by year’s end. The Canadian firm restructured during the summer to focus its efforts around this drug. Additional trials are expected to start the first quarter of 2013 for LCA, and the second quarter of 2013 for retinitis pigmentosa.
AGTC’s Phase I trial for Leber congenital amaurosis (LCA) at the Universities of Pennsylvania and Florida is reporting vision improvements, delivering the RPE65 gene in an adeno-associated viral vector. Preclinical studies by RetroSense Therapeutics indicates that DNA from blue and green algae, delivered to the retina, may restore vision.
The U.S. market for glaucoma therapeutics was approximately $2 billion in 2010. “The gold standard in glaucoma treatment is being challenged by new mechanisms that increase the outflow of fluid, slow fluid production, or control both,” Deborah Toscano, senior industry analyst for pharmaceuticals and biotechnology, Frost & Sullivan, says.
For example, Aerie Pharmaceuticals, Kowa Pharmaceuticals America, and a collaboration between Novartis and Senju Pharmaceutical each have a rho kinase inhibitor in Phase II trials. “It improves fluid outflow. The goal is to maintain efficacy over time,” Toscano says.
Adenosine receptors are receiving attention. Can-fite Biopharma, Inotek Pharmaceuticals, and a collaboration between Otsuka Pharmaceutical and Acuclea are assessing this approach, Toscano says. Can-fite, for example, is developing an orally available adenosine agonist IB-MECA. This anti-inflammatory is modulated by A3AR and inhibits 11 beta HSD1 hydroxy, thus reducing inflammatory cytokine production. Studies are in or preparing for Phase III trials. Santen Pharmaceutical has a calcium agonist, lomerizine HCI, in Phase II trials to inhibit the progression of visual field defects.
Expect to see continued research in drug delivery mechanisms, as well as a focus on AMD, diabetic retinopathy, and diabetic macular edema to treat an aging and increasingly diabetic population.