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Retinal diseases: Firms see options beyond AMD incumbents

By Brian Orelli

Staff Writer

Monday, August 24, 2015

Without a doubt, wet age-related macular degeneration (AMD) has been a lucrative market for companies. Regeneron Pharmaceuticals Inc. announced $1.2 billion in U.S. sales of Eylea (aflibercept) in the first half of 2015, and Roche AG posted CHF769 million (US$804 million) in U.S. sales of Lucentis (ranibizumab).

"The extreme success of the Lucentis and Eylea launches surprised many at the time but in retrospect highlights the axiom that human vision is a critically important trait that is arguably under-appreciated until it is at risk of being lost," Leerink analyst Joseph Schwartz wrote in a research report on the future of retinal disease.

Companies are seeking to keep the retinal disease momentum going, developing new wet AMD drugs, including those that can work in combination with the current offerings, but they're also turning their focus to other retinal diseases, especially genetically inherited orphan indications.

"We see both a deepening and broadening of investment opportunities, driven by the development of new treatments for age-related retinal diseases on the one hand and genetically defined causes of pediatric blindness on the other," Schwartz wrote.


Eylea's success is partly attributable to the fact that it only has to be injected half as often as Lucentis after the lead-in period, but doctors' willingness to switch from the former standard of care shouldn't be overlooked.

"Relative to many other areas of medicine, retinal surgeons have demonstrated that they are a physician group that is very apt to change their practices very rapidly in response to new treatment options that meet their needs. As a result of potentially large shifts in existing markets and breakthroughs in new markets, the stakes in this field are quite high," Schwartz wrote.

The openness to try new offerings bodes well for the likes of Novartis AG, of Basel, Switzerland, and Irvine, Calif.-based Allergan Inc. that are developing longer-acting anti-VEGF treatments.

Novartis AG's RTH258 is being tested in a 2,800-patient phase III trial vs. Eylea. RTH258 is dosed every 12 weeks after the initial induction compared to every eight weeks after induction for Eylea.

Abicipar pegol, developed by Zurich-Schlieren, Switzerland-based Molecular Partners AG and licensed to Allergan plc, is being tested in an 1,800-patient phase III trial vs. Lucentis. Patients in two arms of the trial will get adicipar pegol – either every eight weeks or every 12 weeks – compared to the third arm where patients will get every-four-week dosing of Lucentis.

While the efficacy has justified moving the drugs into phase III development, earlier trials for both drugs have uncovered potential side effects.

A patient in the phase II trial for RTH258 died of a heart attack following the third injection and there were three patients with profound vision loss in the RTH258 arm, compared to zero in the control arm. It isn't clear whether either issue is drug related.

In the phase II trial for abicipar pegol, the drug caused ocular inflammation rates of as high as approximately 12 percent. Key opinion leaders surveyed by Leerink "believe that to be a contender in this market, which already includes good treatment options, ocular inflammation would have to be 1 percent or less," Schwartz noted.

Rather than seeking to replace Eylea and Lucentis, other firms are developing drugs targeting other proteins that can be used in combination with the current offerings, potentially creating a synergistic effect.

In a phase IIb trial run by Ophthotech Corp., patients receiving Fovista (anti-PDGF) in combination with Lucentis increased the number of letters they could read on the eye chart by a mean of 10.6 letters at 24 weeks, compared to a gain of 6.5 letters for patients receiving Lucentis alone.

New York-based Ophthotech is running three phase III trials to get Fovista approved, two combining Fovista with Lucentis and a third will test the drug in combination with Eylea or off-label Avastin (bevacizumab, Roche AG). Results are expected next year. (See BioWorld Today, June 14, 2012.)

Not to be outdone, Regeneron has its own co-formulation of rinucumab (formerly REGN-2176-3), an anti-PDGFR-beta monoclonal antibody, and Eylea. A proof-of-concept phase II trial is scheduled to begin shortly and read out by the end of next year.


Rather than going after the big wet AMD market, other firms are looking at smaller orphan indications where companies have had plenty of success outside of the retinal space.

"We find the ongoing convergence of the retinal and orphan drug business models very intriguing, as scientific understanding and the means to intervene therapeutically continue to advance," Schwartz wrote. "Many inherited forms of blindness are caused by a single gene mutation that impacts particular cell types, patient populations are readily identifiable, pricing power may be substantial and animal models/neuroimaging technologies may provide important derisking information at an earlier stage of development."

For example, Applied Genetic Technologies Corp. (AGTC), of Gainesville, Fla., is using its adeno-associated virus-based gene therapy to treat a variety of orphan indications that affect vision. "The eye is an attractive target because you only need small amounts of the drug," Jeffrey Chulay, vice president and chief medical officer at AGTC, told BioWorld Insight.

The company's lead product treats X-linked juvenile retinoschisis. The disease, caused by a mutation in the RS1 gene, leads to the splitting of the layers of the retina. The damaged retina results in poor vision, which gets worse during the teenage years, and eventually the fragile retinas result in vitreous hemorrhage or retinal detachment during adulthood.

AGTC expects to have initial efficacy data on seven to nine patients from two of the three dosing cohorts by the end of the year.

The company also expects to have data this year on its treatment for achromatopsia, a genetic disease caused by mutations in CNGB3 and CNGA3, which result in improper function of the cone photoreceptors. While rods help people see in dim light, cones are responsible for seeing in bright lights as well as visual acuity, so patients with achromatopsia have severe light sensitivity and have such poor vision that they're considered legally blind. Data for a trial testing the gene therapy replacement of CNGB3 is expected by the end of the year.

Alkeus Pharmaceuticals Inc. is taking a more traditional small-molecule approach to treating Stargardt disease, which is caused by mutations in ABCA4. The gene codes for the Rim protein that's responsible for transporting vitamin A out of the photoreceptors. Mutations in ABVA4 result in a buildup of vitamin A, which form toxic dimmers that are believed to be partly responsible for vision loss.

Boston-based Alkeus has developed a deuterated form of vitamin A, ALK-001, which forms dimmers five to seven times slower than regular vitamin A. Since the body doesn't produce vitamin A, humans get all their vitamin A from food, so ALK-001 is given as a vitamin replacement therapy, increasing the percentage of ALK-001 in the bloodstream and eye relative to regular vitamin A with the extra vitamin A and ALK-001 passing through the gut. Finding a therapeutic window is relatively easy because "the body naturally controls it for you," Leonide Saad, president and CEO of Alkeus, told BioWorld Insight.

Alkeus is currently enrolling a phase II trial that should complete enrollment toward the end of the year and then require two years to see if ALK-001 is helping patients relative to placebo. The trial could be used as the basis for a regulatory filing if the data are strong enough. "It really depends on the results in the end," Saad said.

While Alkeus waits for the data in Stargardt disease, the company is exploring the use of ALK-001 in other eye diseases where toxic vitamin A dimmers have shown to be a problem, including dry AMD.