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.

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.

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.

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