As the huge worldwide cohort of baby boomers advance into their senior years, the number of people afflicted with various forms of retinal disease continues to grow and the opportunities for companies to develop effective therapies has attracted many new entrants. This article examines the research being conducted by three fledgling drug development companies in the retina space — Opthea, Apellis Pharmaceuticals, and ONL Therapeutics — all of which are at various stages of the development process and all of which have attracted recent significant financial backing.

Both Opthea (based in Australia) and Apellis were recently able to complete major stock offerings on the heels of highly promising early-stage clinical trials — Opthea in wet AMD and Apellis in geographic atrophy. ONL is still on the verge of commencing its first human clinical trial for its neuroprotective agent to prevent cell death in retinal detachment, but ONL has also been able to raise money to meet its initial needs.

Following is a description of each company’s history, research efforts, and management credentials.

OPTHEA

A major part of Opthea’s appeal is that its intravitreally delivered OPT-302 combats VEGF C and VEGF D, making it potentially highly complementary to combine with either Lucentis (ranibizumab, Genentech) or Eylea (aflibercept, Regeneron), which attack VEGF A. Pravin U. Dugel, MD, lead investigator for the early-stage OPT-302 clinical trials, has called this a “pan-VEGF approach.”

In 2017, Opthea took a major step toward creating a larger footprint with the release of across-the-board positive data from its 12-week, 51-patient phase 1/2a study that evaluated OPT-302, its fusion protein “trap” therapy in the treatment of wet AMD. The drug was investigated as both monotherapy and in combination (two injections given 30 minutes apart) with Lucentis. These early-stage results were so compelling in both mono- and combination therapy that Opthea was able to quickly close on an oversubscribed $45 million (Australian dollars) offering to fund three additional clinical trials and keep the company fully funded until 2021.

The new studies consist of a 350-patient phase 2b trial for treatment-naïve wet AMD patients in combination with Lucentis (begun in December), a smaller phase 2a trial for previously treated wet AMD patients, and a 117-patient phase 1b/2a trial in combination with Eylea for patients with DME (begun in January).

The science behind OPT-302, Opthea’s only investigational drug candidate, is based on initial research efforts at the University of Helsinki and the Ludwig Institute for Cancer Research in Melbourne (both now Opthea shareholders), which formed a basis for continued internal development and optimization of the drug at Opthea.

“As a fusion protein with a ‘trap’ mechanism of action, OPT-302 bears some similarities to Eylea, but Eylea targets VEGF-A and our drug targets VEGF-C and VEGF-D that are novel members of the VEGF family,” says Opthea CEO Meg Baldwin, PhD.

The phase 1/2a trial, though small and early-stage, demonstrated that OPT-302 was well tolerated following three monthly intravitreal injections in both treatment-naïve and previously treated patients. The latter group was considered “difficult to treat” after demonstrating a disappointing response to prior anti-VEGF-A therapy. Monthly OPT-302 also demonstrated clinical activity in all patient groups investigated, with improvements in visual acuity and reductions in subretinal fluid over the 12-week trial.

Opthea is considered to have excellent leadership as it moves forward with later-stage clinical trials. Dr. Baldwin joined the company in 2008 after gaining valuable research and business experience at Genentech.

Being at the head of a company focused on biologic treatments for retinal disease was a perfect fit for Dr. Baldwin, who spent 5 years at Genentech, first as a researcher working with the team of Napoleone Ferrara, MD, who discovered VEGF-A, and 2 years gathering business experience in market planning on the company’s commercial side. Her time at Genentech provided her with a set of skills well-suited to an entrepreneur.

APELLIS PHARMACEUTICALS

Apellis has made a full commitment to its complement inhibitor APL-2 for a range of both ocular (geographic atrophy and wet AMD) and non-ocular indications. The company gained positive attention in 2017 with a promising phase 2 clinical trial in geographic atrophy and subsequently raised $150 million in a public stock offering.

Apellis has already announced the outlines of its upcoming phase 3 trial in geographic atrophy, slated to begin later this year. The company plans to continue along similar lines as its successful phase 2 trial, aiming to reduce disease progression with complement inhibition at the C3 level, but with a much larger patient cohort than was studied in phase 2. One issue that cropped up in the phase 2 trial was a significant incidence of wet AMD. There have been several possible explanations for this side effect — wet AMD in the fellow eye is one — but nothing definitive has been proven yet.

In the phase 2 246-patient FILLY trial, APL-2, met its primary endpoint in patients with geographic atrophy (GA) associated with AMD. At 12 months, APL-2, administered monthly via intravitreal injection, showed a 29% reduction in the rate of GA lesion growth compared to placebo. With every other month administration, a 20% reduction was observed.

Additionally, in a post-study analysis, a greater effect was observed during the second six months of the study: a reduction in growth rate of 47% with monthly administration, and a reduction of 33% with every other month administration. Apellis believes this finding of increasing effectiveness over time is a potentially important positive for the drug.

At 18 months, 6 months after treatment was ended, APL-2 was still showing residual effectiveness over placebo, the company reported.

The most frequently reported adverse events in the study eye were associated with the injection procedure.

A higher incidence of wet AMD was observed in the treatment groups, predominantly in subjects with a history of wet AMD in the fellow eye and was managed with the administration of standard-of-care anti-VEGF therapies.

“In this real-world phase 2 study, we enrolled patients with geographic atrophy regardless of the fellow eye status and regardless of the autofluorescence patterns, and the only restriction was the size of the lesion,” commented investigator Philip Rosenfeld, MD, PhD, of Bascom Palmer Eye Institute. “We included almost all patients as long as they saw better than 20/320. And, we included patients with exudative neovascularization in the fellow eye. In the past, many of these patients had been excluded from these clinical trials.”

“We are very excited about the results of this study,” said Cedric Francois, MD, PhD, founder and CEO of Apellis. “In addition to demonstrating a statistically significant slowing of disease over 12 months, APL-2’s effect appears to increase in the second 6 months of the study, slowing down the rate of degeneration by almost half.”

APL-2 is the product of more than 12 years of development and improvement by the Apellis scientific team, with a goal of making the drug effective in both wet AMD and geographic atrophy.

ONL THERAPEUTICS

David Zacks, MD, PhD, of the Kellogg Eye Institute at the University of Michigan, has spent more than 15 years studying photoreceptor cell death in the eye and concluded that inhibiting the FAS pathway through an appropriate medical therapy is key to stopping unwanted photoreceptor cell death in retinal detachment, wet and dry AMD, geographic atrophy, and diabetic retinopathy.

Though the first human clinical trials of the company’s neuroprotective ONL1204 peptide drug are still a few months away, Dr. Zacks and his team have already attracted a highly respected scientific advisory board that has confidence the dramatic results attained in preclinical animal studies will be transferable to humans. The target for the initial trial is the 25,000 annual US cases of “macula-off” retinal detachment. This is a serious, emergency event for which surgical results have been excellent but visual outcomes almost uniformly poor, with average BCVA at 1 year after surgery at 20/70, with many patients’ visual outcomes much worse than that.

“The photoreceptor cell death that takes place between the time the retinal detachment occurs and the reattachment surgery is significant,” says Dr. Zacks. “That lost vision is not being regained. Our goal is to get our ONL1204 drug (an analog of the small-molecule peptide Met12) injected into the patient’s eye as quickly as possible to shut off the FAS pathway and stop the cell death, which should allow much better visual outcomes in retinal detachment surgery.”

Dr. Zacks says ONL1204 should also be able to provide neuroprotection in a range of common retinal diseases, treating the root cause of vision loss, which is photoreceptor cell death. Overall, the potential market opportunity for the use of ONL1204 in a variety of indications exceeds $12 billion annually. The FDA has already given ONL1204 orphan drug designation.

As Dr. Zacks’ long-term research on the role of the FAS pathway in photoreceptor cell death continued to progress, he accumulated a great deal of valuable intellectual property from his time at both Kellogg and previously at Massachusetts Eye and Ear.

“I recognized that we had a potential therapy, but I did not know how to make drugs, and I knew that I needed help to move ahead,” says Dr. Zacks. “I got great support from my department and from the University of Michigan’s mentor-in-residence and technology transfer programs. At that point, we decided to form a company (ONL is an acronym for ‘outer nerve layer’) as the best way to move ahead and to ensure that all interests were aligned.”

In a recent interview with Retinal Physician, Dr. Zacks said that both funding for the trial and recent preclinical research have been going well and expressed a high level of confidence in the potential of ONL1204.

“We raised $5 million in Series A financing to take us to the IND filing around mid-year and we anticipate additional Series B funding to conduct the dose-escalation trial, which will eventually encompass about 100 patients. Our research has been very promising. We’ve learned a great deal about keeping cells alive.”

Dr. Zacks says designing the trial is a challenging task that is taking a great deal of thought.

“The trial design will be critical,” he asserts. “For example, how do we define success?”

Another challenge is conducting the trial. Patients will come into the clinical sites as emergency cases and must be treated within hours of the retinal detachment.

“We need to have clinical sites that have some volume of these cases,” he says. “It costs money to set up each clinical site, so you want to have active sites that provide patients for the study.”

ON THE HORIZON

As the number of retinal diseases continues to rise, companies will continue to develop innovative therapies to help combat the various forms. NRP