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SUBSPECIALTY NEWS

SUBSPECIALTY NEWS

Drug Developers View Ang2 as Target

Leaders see beyond anti-VEGF monotherapy.

BY JERRY HELZNER, CONTRIBUTING EDITOR

■ Leading developers of drugs for retinal disease — including Regeneron, Roche/Genentech, and Aerpio — are pursuing what could become one of the most promising breakthroughs against retinal disease in years. All three companies are currently conducting phase 2 clinical trials designed to combat the vascular growth factor Angiopoietin2 (Ang2), which has been identified as a contributor to TIE-2 pathway disruption and the unwanted blood vessel formation that characterizes retinal disease. One aspect of all the trials is to determine if the Ang2 inhibitor can be successfully paired with a currently approved anti-VEGF drug to achieve better outcomes than anti-VEGF monotherapy.

As one example of early but promising Ang2 inhibition, Aerpio (Cincinnati) reported that its AKB-9778 small molecule, which restores proper functioning of the Tie2 receptor by attacking a tyrosine phosphatase enzyme, had successful three-month results. An AKB-9778/Lucentis (ranibizumab) combination outperformed Lucentis monotherapy in both DME and diabetic retinopathy. The unwanted enzyme is part of the Ang2 signaling pathway.

The Roche Ang2 inhibitor, known as RG7716, is a bispecific antibody currently in the 36-week, 271-patient AVENUE trial for wet AMD. This larger study follows encouraging results with suboptimal anti-VEGF responders in a small, 24-patient trial in the UK. One arm of the multi-arm AVENUE study is a combination of RG7716 and Lucentis. For its part, Regeneron recently announced two new trials for its Ang2 antibody in coformulated combination with its anti-VEGF drug Eylea (aflibercept). The trials are for wet AMD and DME.

As developers of two of most successful therapies in recent pharmaceutical history — Eylea and Lucentis — one might think that both Regeneron and Roche/Genentech would be content to rest on their current dominant positions in anti-VEGF monotherapy for a range of retinal diseases. But that’s not the case. With credible challengers coming at them from many directions (including the new class of biosimilars), both companies are pursuing aggressive new investigational initiatives to advance their offerings beyond anti-VEGF monotherapy.

Regeneron now has under way several trials for retinal disease combining Eylea and either an anti-PDGF or an Ang2 inhibitor in a single coformulated injection. As part of its major emphasis on genetics, the company also has major partnerships in both gene replacement therapy with Avalanche Biotechnologies (Menlo Park, CA) and in gene editing with Intellia (Cambridge, MA). These partnerships may eventually encompass both ophthalmic and non-ophthalmic therapies.

Meanwhile, in addition to the RG7716 program, Genentech has initiated a phase 2 study called LADDER for the sustained-release delivery of Lucentis via a tiny, implanted, refillable reservoir. The company believes that Lucentis has the stability to be suitable for a sustained-release format.

IN BRIEF

AngioVue Retina now available. Optovue, a leader in the development of both OCT and OCT angiography (OCTA), announced the immediate availability of AngioVue Retina, a proprietary imaging system that provides retina specialists with a non-invasive, dyeless way to quickly visualize blood flow and microvasculature in the retina in great detail.

AngioVue Retina, which recently received FDA clearance, is configured with essential OCT and OCTA features designed specifically for retinal practices to allow adoption of OCT and OCTA into the clinical workflow with minimal disruption.

Clearside has public stock offering. Clearside Biomedical (Alpharetta, GA), which specializes in the delivery of ophthalmic drugs via the suprachoroidal space, completed its initial public stock offering in early June, raising $50.4 million. The shares now trade on NASDAQ under the symbol CLSD.

Iridex supports “Eyes of Africa.” Iridex has donated an 810-nm OcuLight SLx multi-functional laser suitable for retinal photocoagulation and glaucoma procedures to the “Eyes of Africa” blindness-prevention program in Malawi, where preventable blindness is a major problem.

Opthea Has “Pan-VEGF” Approach to Wet AMD

OPT-302 inhibits three types of VEGF.

■ Opthea (Melbourne, Australia) has just begun a phase 2a clinical trial in wet AMD for its proprietary drug OPT-302, which combats VEGF-A, VEGF-C, and VEGF-D, while not inhibiting the “good” neuroprotective VEGF-B. The Opthea wet AMD drug offers the promise of pan-VEGF inhibition, especially when used in combination with either Lucentis or Eylea.

A 20-patient dose-escalation phase 1 study demonstrated an excellent safety profile as both monotherapy and in combination with Lucentis. OPT-302 has now moved into a 30-patient phase 2a study that will encompass such factors as efficacy and durability, as well as determining an ideal dose. The 2a trial also features a monotherapy arm and a combination arm, again with Lucentis.

Lead investigator Pravin Dugel, MD, of Retinal Consultants of Arizona, says the early-stage results for safety and biological response have been encouraging but no conclusions can yet be drawn for efficacy and durability.

“We will be finding out more about those aspects of the drug in the phase 2a study,” he says.

Dr. Dugel notes that what intrigues him the most about the Opthea drug is that it represents an effort to achieve pan-VEGF inhibition, attacking three types of VEGF (A, C, and D) that contribute to the development of wet AMD. Used in combination with Lucentis or Eylea, which both combat VEGF A, OPT-302 may have unique therapeutic capabilities not seen in previous AMD drugs.

“It’s also encouraging is that OPT-302 does not inhibit VEGF B, which offers the neuroprotective qualities that we want to retain,” says Dr. Dugel.

IN BRIEF

Early treatment for DME benefits patients. A new study indicates that people with less advanced DME and who responded better to initial treatment with Lucentis (ranibizumab, Genentech) needed fewer injections over the long-term, suggesting that treating people with DME earlier may help reduce long-term treatment burden. The study, conducted by researchers led by Charles Wykoff, MD, PhD, was presented in a recent issue of Ophthalmology.

In a retrospective analysis of the phase 3 RIDE and RISE clinical trials, baseline demographics, disease characteristics, and treatment responses to Lucentis were examined as predictors of long-term injection frequency during the studies’ open-label extension (OLE) period. Five hundred patients were enrolled in the OLE after completing the 36-month RIDE and RISE studies and were eligible to receive 0.5 mg doses of Lucentis on a PRN basis according to pre-defined criteria.

In the analysis, 121 patients required no treatment, 132 required up to three annualized injections, 159 required more than three but no more than seven injections and 88 required more than seven injections. Researchers found that compared to those who needed more than seven injections, patients who required zero injections during the OLE had, on average, a shorter duration of diabetes and DME at baseline, were less likely to have PDR at baseline, received fewer laser treatments and were more likely to experience a greater improvement in DR severity.

Regeneron to sponsor Science
 Talent Search. Regeneron (Tarry-town, NY) has announced that it will be the new title sponsor of the national Science Talent Search (STS) for high school science students. The company, which takes over primary sponsorship from Intel, has made a 10-year commitment to the contest totaling $100 million.

One of Regeneron’s first moves was to nearly double the annual prize money to $3.1 million, including a $250,000 first prize, up from $150,000 last year.

Two of Regeneron’s top executives, CEO Leonard Schleifer, MD, PhD, and Chief Scientific Officer George Yancopoulos, MD, PhD, were high school science prodigies in the 1970s who received STS recognition. Regeneron’s goals in committing to the sponsorship are to keep students in science, raise the image of biotech, and encourage future science stars who might want to work at Regeneron.

Acucela oral drug fails in GA. Acucela Inc. said its oral visual cycle modulator emixustat hydrochloride failed to show significant differences from placebo in a 508-patient phase 2b/3 clinical trial for geographic atrophy.

None of the three dose sizes of emixustat (10.5 mg, 5 mg, and 2.5 mg) were able to demonstrate superiority to placebo at 24 months in either lesion growth or BCVA.

Iluvien Effective in “Real World” Study

DME implant helps after anti-VEGF fails.

■ Alimera Sciences Limited, the European subsidiary of Alimera Sciences (Atlanta), said real-world data shows that the majority of DME patients who received the Iluvien implant (fluocinolone acetonide 190 micrograms) in routine clinical practice gained or maintained vision at 12 months.

In contrast with the pivotal clinical trials known as the FAME studies, where all patients had prior laser therapy and few had received anti-VEGF therapies, in the Iluvien Registry Safety Study at least two-thirds are known to have received prior anti-VEGF injections. Despite these prior treatments, patient vision outcomes, IOP increases, and other side effects were comparable to the FAME results.

“It is exciting to see that the Iluvien real-world data in Europe in patients who are primarily refractory to anti-VEGF therapy mirror FAME results several years later after the emergence of changing treatment patterns with anti-VEGF therapy,” said Dan Myers, Alimera’s chief executive officer.

Professor Usha Chakravarthy from Queens University Belfast, principal investigator of this post authorization study, said: “In these real-world studies, patients were switched to Iluvien when clinicians had determined that despite other treatments there was vision decline and worsening appearance of the macula. Following the switch, there were improvements in visual acuity and retinal morphology in the majority of patients showing that Iluvien is an important addition to our therapeutic armamentarium.”

The data were revealed for the first time at the recent Royal College of Ophthalmologists (RCOpth) annual congress in Birmingham, England.

The Iluvien Registry Safety Study is a post-authorization safety study that Alimera is required to perform in Europe. Interim data presented at the RCOpth Congress is from 328 eyes (292 patients) from 25 centers in the U.K., 10 in Germany and one in Portugal. This study collects primary data on safety and some visual acuity, but no data from OCT.

Vision improved in 58.0% of Registry Safety Study patients at 6 months and 61.0% at 12 months, which is comparable with the FAME trials. Mean visual acuity increased from 50.9 letters at baseline to 55.7 letters at six and 12 months, with 15.9% of patients gaining ≥15 letters at 6 months and 20.8% of patients gaining ≥15 letters at 12 months. 27.0% of patients at 6 months and 34.0% at 12 months regained vision that was better than 20/40, which is often a minimum requirement for driving.

In this study, unlike FAME, some patients were on IOP-lowering medications prior to Iluvien use. Interim results from this European study show that 81.6% of patients required no new or additional IOP-lowering medication, 9.9% had an IOP increase of
≥10 mm Hg and 8.2% had an IOP elevation of above 30 mm Hg. Regarding cataract formation, among the 51 phakic eyes treated in the study, 14 (27.4%) underwent cataract surgery for an existing cataract concurrent with their Iluvien injection, five (9.8%) developed a cataract on Iluvien, and 10 (19.6%) underwent cataract surgery for existing or new cataracts.

IN BRIEF

Second Sight raises $19.4 million for initiatives. Second Sight Medical (Sylmar, CA) said it has raised net proceeds of $19.4 million through a stock rights offering that allowed current shareholders to purchase additional shares at a discount. The funds will be used for a number of corporate initiatives, including continued development of the Argus II retinal prosthesis for both retinitis pigmentosa and dry AMD, the development of the Orion Visual Cortical Prosthesis to address almost all forms of blindness, and for general corporate purposes.

Eylea label change. The FDA has approved a label change for Eylea (Regeneron), a leading anti-VEGF drug for a range of retinal diseases. The label has been changed to state that while most wet AMD patients should be dosed 2 mg every eight weeks after three initial monthly doses, some patients may require dosing at four-week intervals. This despite the fact that clinical trials have shown no additional efficacy for most patients when dosed every four weeks.

The label change for DME and diabetic retinopathy is similar, although five initial monthly doses are required rather than the three for wet AMD.

Humira Approved for Noninfectious Uveitis

Systemic, nonsteroidal approach breaks new ground.

■ The FDA on June 30 approved the use of Humira (adalimumab, AbbVie) for the treatment of noninfectious intermediate, posterior, and panuveitis in adult patients. The company says Humira, a systemic, biologic therapy given Orphan Drug status by the FDA in 2014 for certain forms of noninfectious uveitis, is now the first and only FDA-approved noncorticosteroid therapy for these indications.

Humira was the first fully human monoclonal antibody biologic drug ever to be approved by the FDA. It is a tumor necrosis factor (TNF)-alpha inhibitor that produces an anti-inflammatory response in the immune system. Because it suppresses TNF, which is part of the immune system, patients on Humira may have reduced resistance to infections such as tuberculosis viruses, and bacteria, making it important that potential patients for the drug be screened carefully and monitored closely.

The drug had previously been approved by the FDA and also worldwide for a number of indications, including rheumatoid arthritis, ulcerative colitis, and Crohn’s disease, achieving several billion dollars in annual sales. It is given by subcutaneous injection and is generally self-administered, as it was in the two pivotal clinical trials for the uveitis indication.

Emmett T. Cunningham, Jr., MD, PhD, MPH, of West Coast Retina in San Francisco, notes that anti-TNF-class drugs such as Remicade (infliximab, Johnson & Johnson) have often been used off-label for uveitis as second-line therapy after the anti-metabolite methotrexate in steroid-sparing treatment regimens. He has also coauthored a paper called “The Promise and Limitations of TNF-alpha Inhibition for Uveitis” (in Ocular Immunology and Inflammation in 2014). The paper looks at several studies involving the use of anti-TNF-alpha agents to combat various forms of uveitis, including Beçhet disease and uveitis associated with juvenile idiopathic arthritis. The authors conclude that, while anti-TNF-alpha drugs show efficacy, the rate of recurrence after stopping the anti-TNF agent is generally quite high, in some studies 60% or more.

“The TNF-alpha inhibitor drugs are expensive (approximately $3,000 per month) and it has often been difficult to get payment authorization,” he says. “Copay can also be difficult and as these drugs have been used off-label the pharmaceutical companies don’t really have any programs in place to help patients with uveitis who have difficulty with the copay. The hope in the retina community is that this approval will help facilitate patient access.”

The FDA approval for uveitis was based on two large-scale, placebo-controlled clinical studies — VISUAL-I and VISUAL-2 — which encompassed an initial 80-mg baseline loading dose and 40 mg injected subcutaneously every other week for up to 80 weeks, or until treatment failure occurred. AbbVie says the Humira label for uveitis will call for the same dosing and timing as was used in the clinical trials, as well as subcutaneous self-administration.

The primary endpoint of both VISUAL-I and VISUAL-II was time to treatment failure. In the 217-patient VISUAL-I trial, median time to treatment failure was 3 months for placebo and 5.6 months for Humira, with median time to failure prolonged by 87% in the Humira cohort. Humira data was even better in VISUAL-II, with more than half of the patients who received Humira never experiencing treatment failure at all, making time to failure for Humira moot in this trial.

“These approvals provide a valuable option for patients experiencing flare and vision impairment associated with this group of inflammatory diseases of the eye,” said Glenn J. Jaffe, MD, of Duke University, Durham, NC. “Data from the robust VISUAL clinical trial program demonstrate the value of Humira as a treatment option for patients with these serious diseases.”

Michael Singer, MD, of Medical Center Ophthalmology Associates in San Antonio, sees the Humira approval as “a good thing, as it increases the armamentarium for treating this disease.” However, he cautions that ophthalmologists who do not specialize in uveitis may have trouble becoming familiar with using Humira as a systemic therapy.

“In general, retina specialists who do not handle complex uveitis cases will still be reticent to try a systemic medication,” says Dr. Singer. “The company would be well-advised to spend time educating retina specialists on the value of immune therapy given systemically, so there would be a higher adoption rate for this new and promising indication for this medication.”

Subcutaneous self-administration has recently become a more prevalent method of drug delivery in the ophthalmic realm. Aerpio Therapeutics recently completed a successful phase 2a trial for its proprietary DME and diabetic retinopathy drug AKB-9778. The company reported that with brief training patients were comfortable with subcutaneous self-administration of the drug. RP

IN BRIEF

Already diluted Jetrea approved. ThromboGenics (Brussels, Belgium) announced that the Food & Drug Administration has approved an “already diluted” form of Jetrea for the treatment of vitreomacular adhesion (VMA). The new format, scheduled for launch in the first half of 2017, eliminates the preparatory steps used to dilute the current Jetrea formulation. The already-diluted format maintains the strength, potency, composition, and pharmaceutical form of the currently available formulation that is injected following dilution.

Eleven Bio licenses IL-6 inhibitor to Roche. Eleven Biotherapeutics (Cambridge, MA) has granted a worldwide exclusive license of its monoclonal antibody EBI-031 to Roche for a combination of an upfront payment, milestone payments, and potential future royalties. Eleven says EBI-031 potently binds interleukin-6 (IL-6) and inhibits all known forms of IL-6 cytokine signaling.

As part of a comprehensive agreement with Roche relating to its IL-6 technology, Eleven has also filed an Investigational New Drug (IND) application with the FDA to begin clinical trials for EBI-031 as a an intravitreally delivered treatment for DME and uveitis. In addition to an upfront payment of $7.5 million, Eleven stands to receive a minimum of $20 million when the IND becomes effective and future milestone payments that could reach $262.5 million.

Grapes may ward off retinal disease. Compounds found in grapes may help protect against eye disease, according to new preclinical research led by researchers at the Bascom Palmer Eye Institute at the University of Miami Miller School of Medicine. The study, published in the journal Nutrition, showed that a diet supplemented with grapes was able to counter damage from oxidative stress and preserve retinal structure and function in a laboratory model of retinal degeneration.

An antioxidant compound in grapes and red wine called resveratrol has long been credited with having protective benefits against heart disease.

“Adding grapes to the diet actually preserved retinal health in the presence of oxidative stress in this study,” said Abigail S. Hackam, PhD, associate professor of ophthalmology at the Miller School, and lead investigator of the study. “These results are very exciting and build on the growing evidence that suggests a compound in grapes is beneficial to eye health.”

Natural components in grapes that help promote antioxidant activity are thought to be responsible for these beneficial effects, in keeping with previous studies that indicate grape-derived compounds are biologically active in the retina.

Shire ROP drug has mixed results. Shire plc (Dublin, Ireland) said its phase 2 study evaluating an investigational protein replacement, SHP607, did not meet its primary endpoint of reducing the severity of retinopathy of prematurity (ROP).

The study, however, demonstrated clinically relevant effects in secondary endpoints related to the development of severe bronchopulmonary dysplasia (BPD), a chronic lung disease, and severe intraventricular hemorrhage (IVH), a type of brain injury, both of which have lifelong negative implications for normal development

SHP607 is a recombinant human version of the naturally occurring protein complex of insulin-like growth factor 1 (IGF-1) and its most abundant binding protein, IGF binding protein-3 (IGFBP-3).

The phase 2 study included 121 extremely premature infants (born between 23 weeks and 27 weeks +6 days) randomized at birth to either SHP607 or standard neonatal care and treated continuously until an equivalent gestational age of 30 weeks. IGF-1 is a growth factor that plays a major role in the development of the growing fetus in the uterus. It is supplied by the mother until about 30 weeks of gestation, when the fetus begins producing the growth factor on its own. Levels of IGF-1 dramatically decrease in infants born extremely premature (before 28 weeks of gestation), thereby increasing the risk for complications related to the lungs, brain, eyes, and other organs.

“This is the first controlled clinical trial to confirm the crucial role of IGF-1 in maturation of extremely preterm children,” said Professor Neil Marlow of the University College London Hospitals, UK, and one of the clinical trial investigators. “The reduction in BPD and IVH, as the two most important morbidities suffered by these children, are welcoming and a first in neonatal medicine. It will be important to confirm these findings in additional clinical studies.”

Philip J. Vickers, PhD, Head of Research & Development, Shire, said, “Although the study did not meet its primary endpoint, we are extremely encouraged by the topline secondary endpoints related to lung and brain. For severe complications related to the lung and brain, there are no approved treatment options, and these data support our commitment to further investigate the potential systemic benefits of SHP607 in this population where the unmet patient need is substantial.”

Later this year, Shire expects to begin discussions with regulatory authorities about a phase 3 clinical program focusing on clinically relevant complications of prematurity.