Boomer Alert: Aging immune cells increase risk for macular degeneration, blindness. Apellis, Ophthotech to the rescue?

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The News:

As people age, so do their immune systems. And new research at Washington University School of Medicine in St. Louis suggests that aging immune cells increase the risk for age-related macular degeneration, a major cause of blindness in the US. Studying mice and cells from patients, the researchers found that as immune cells called macrophages age, they are more likely to contribute to the inflammation and abnormal blood vessel growth that damage vision in macular degeneration.

“Drug treatments for macular degeneration aren’t effective for some patients, who either have a minimal response or not response at all, and many patients continue to experience vision loss over the long term, even if they have a good initial response to treatment,” said senior investigator Rajendra S. Apte, MD, PhD, the Paul A. Cibis Distinguished Professor of Ophthalmology and Visual Sciences. “But by understanding what happens with the immune cells in the eye, it may be possible to develop therapies to help patients who can’t be helped with existing drugs.”

In experiments in mice, Apte’s team found that older macrophages carry larger amounts of short snippets of genetic material, called microRNAs, that govern how cells express genes. The researchers found significantly higher levels of microRNA-150 in macrophages in the eyes of older mice.

MicroRNAs help regulate many things in cells by binding to several genes to influence how those genes make proteins. In this study, the researchers found that microRNA-150 seemed to be guiding older macrophages toward promoting inflammation and abnormal blood vessel formation in a mouse model of macular degeneration.

The researchers also tested blood samples from human subjects with and without macular degeneration. The samples from those with macular degeneration also had significantly higher levels of microRNA-150 in their macrophages.

“We think microRNA-150 may be a potential therapeutic target, or at least a biomarker, for aggressive disease and risk of vision loss,” said first author Jonathan B. Lin, an MD/PhD student at the School of Medicine.

Lin and Apte said if they could somehow reduce microRNA levels in macrophages, or alter one or more molecular pathways regulated by this microRNA, they might be able to lower levels of inflammation and interfere with abnormal blood vessel growth in the eye. They also believe similar strategies eventually may help patients with other diseases related to aging.

“It’s possible to envision immune-based therapies that would tweak the level of microRNAs so that these macrophage cells no longer contribute to disease,” said Apte. “If we could make these older cells more like the younger ones, we might be able to prevent a great deal of vision loss.” Their findings are published April 5 in the journal JCI Insight. (Ref: News-Medical.Net)

Steve’s Take:

In the same vein as treatments for auto-immune disease, another major disease category, mostly ignored by analysts because drug developers also don’t seem to care, is age-related macular degeneration (AMD).

Among those who do care are the 11 million Americans who currently have some form of AMD and are expected to top 22 million by 2050. One early symptom is blurry vision in which straight lines appear distorted. That can progress to darkness, whiteouts or blurry areas in the center of the visual field.

Yes, currently there are several effective treatments available for wet age-related macular degeneration (wAMD). But as the above report from Washington University School of Medicine points out, the market still lacks treatments for dry AMD (dAMD), which is a significant unmet need of the AMD space.

How significant?

GlobalData estimates that over 69 million people had some form of dAMD in 2016 across the seven major markets, which includes the US, France, Germany, Italy, Spain, the UK, and Japan. Nearly as many AMD patients presented with the late-stage or atrophic form of dAMD, called geographic atrophy (GA), as those with wAMD. GA is typically a bilateral disease, making this AMD segment potentially even more lucrative than wAMD, which GlobalData estimated was worth $4.9 billion in 2016 across these countries.

Now, a new report finds that pharmaceutical sales within the age-related macular degeneration (AMD) markets could reach $11.5 billion across the seven major markets by 2026, growing at nearly 9% on an annual basis, says The Pharma Letter.

Novartis AG has acquired strong Phase 3 data for its AMD candidate RTH258 (brolucizumab). Meanwhile, Regeneron Pharmaceuticals Inc.’s patent for Eylea (aflibercept) expires in 2020 in the EU, where it’s licensed to Bayer AG, and 2021 in the USA.

GlobalData analyst Edit Kovalcsik said: “We expect that with the launch of brolucizumab in the wAMD market, Novartis will offset the losses to Eylea and regain dominance in the AMD market.”

Once more efficacy and safety data accumulate and physicians become more accustomed to the use of brolucizumab, its advantage of less frequent dosing will allow it to claim an increasing share and become a first-line therapy if reimbursed.

The analyst forecasts that brolucizumab will reach blockbuster status by 2021 and will be the highest selling drug by 2026 among all drugs launching to the AMD market, with $4.1 billion in global sales.

Research has highlighted a link between complement protein polymorphisms and the development of AMD. Despite numerous pharmaceutical and biotechnology companies targeting the complement pathway, however, no product of this type has reached the market.

The disappointing result of the Phase 3 lampalizumab trial announced on September 8, 2017 decreased earlier optimism surrounding Roche Holding AG’s anti-complement program, although results of the second Phase 3 trial, Chroma, remain to be revealed in November 2017.

Around the same time as this discouraging anti-complement news, Apellis Pharmaceuticals Inc. (Crestwood KY) announced that APL-2, a complement C3 inhibitor, met its primary endpoint of slowing the rate of GA lesion growth in patients with GA due to AMD, and that the company is planning to initiate the Phase 3 program of APL-2 in GA as soon as possible.

In the knowledge of its competitors’ recent conflicting pipeline results, Roche’s lampalizumab and Apellis’s APL-2, Ophthotech Corp. (NYC) decided to continue its Zimura program. Zimura is a complement C5 inhibitor, which blocks all three complement pathways (similar to APL-2), while lampalizumab blocks only the alternative complement pathway through targeting complement factor D.

Bottom Line:

With its accelerated program, Ophthotech’s Zimura is definitely a drug to look out for in the dAMD space; however, with the lack of interim data, it’s hard to predict its efficacy. Nonetheless, according to key opinion leaders, Zimura could be even more successful than lampalizumab, because it has a broader target; specifically, it is not restricted to the CFI mutation-positive GA population. While APL-2 has shown efficacy in the Phase II trial, its utility in dAMD will also need to be proved by large-scale Phase 3 trials.

Ophthotech also aims to leverage from Zimura in wAMD within the AMD space, and has announced the initiation of a Phase 2a trial of Zimura in combination with Lucentis, in the hope that complement inhibition during anti-VEGF therapy may have therapeutic benefit over anti-VEGF monotherapy.

Steve's Take: Keep an eye out on #Ophthotech, a great buying opportunity could be in the offing Click To Tweet

GlobalData believes that the companies that manage to set foot in the dAMD space in the next 10 years will benefit substantially from this market, with their drugs potentially reaching blockbuster status within four to five years of launch.

Provided efficacy is demonstrated, I agree with analysts who believe that with its complement inhibitor, Ophthotech could arise as a frontrunner of the dAMD space, although there will be plenty of opportunities for the other companies to carve out a generous slice of this foreseeable highly-lucrative market.

Cash balance

Ophthotech’s cash balance was $167 million as of Dec 31, 2017.

The company provided its expectation of cash burn to fund its operations in 2018 to be in the range of $50 million to $55 million, so it’s got plenty of room to run even without another funding round. Ophthotech carries a Zacks Rank #3 (Hold).

I’ll be keeping an eye on this company. A great buying opportunity could be in the offing, so stay tuned as trial results pour in later in the year.

Steve Walker has no position in any stocks mentioned. MedContent Inc. has no position in any stocks mentioned. has a disclosure policy.

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