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June 2, 2022

Fewer dry AMD clinical trials than wet variety despite no treatment options

Luxa Bio offers a sneak peek of its Phase IIb dry AMD trial plans targeted for H2 2023 or 2024.

By Urtė Fultinavičiūtė

Age-related macular degeneration (AMD) is a leading cause of visual disability. Aging can lead to damage to the eye’s macula, which then can progress to blurred central vision.

With a growing aging population, the number of people worldwide with some form of AMD is expected to reach 288 million by 2040. While AMD’s market size in 2020 decreased by $490 million to $9 billion due to the Covid-19 pandemic, it is forecasted to rebound to $19.8 billion in 2028, according to GlobalData.

There are two types of AMD: dry and wet AMD, with the latter leading to quicker loss of vision. Dry AMD is the more common variety, accounting for 70–90% of all AMD cases. Yet, there are no treatment options, with available approaches, such as dietary supplements, only delaying degeneration. As such, patients eventually progress to late dry AMD.

Patients with dry AMD can also progress to wet AMD. Wet AMD has more therapeutic options available, such as anti-VEGF drugs and photodynamic therapy (PDT). Further, wet AMD has more ongoing clinical trials compared to dry AMD, according to GlobalData’s Clinical Trial Database. GlobalData is the parent company of Clinical Trials Arena.

“[Dry AMD] is not a rare disease, but it is very prevalent with no treatment,” says Luxa Biotechnology co-founder Dr Jeffrey Stern, whose company has a dry AMD candidate in a clinical trial.

AMD research is led by the industry

In dry AMD, there are 34 planned or ongoing clinical trials and majority of these trials are still in early stages, with 11 in Phase I. Stern notes there are pharma companies focusing on dry AMD biologics and small molecules, designed to slow down atrophy of retinal pigment epithelium (RPE) cells.

Clinical trials in dry AMD are mostly sponsored by the pharma industry: 25 of the planned or ongoing trials are industry-led.

Zooming into the pipeline, there are two forthcoming clinical trial readouts in dry AMD expected before the end of the year: NGM Biopharmaceuticals’s Phase II asset NGM-621, and Iveric Bio’s Phase III candidate ARC1905.

NGM’s 320-participant Phase II NGM-621 trial (NCT04465955) has a primary efficacy endpoint measuring the lesion change in advanced dry AMD, known as geographic atrophy (GA). NGM-621 is designed to inhibit complement component 3 (C3), which could potentially slow down degeneration in the macula.

Meanwhile, Iveric’s 448-subject Phase III ARC1905 trial (NCT04435366) has a primary endpoint of mean rate of GA change. ARC1905 is a complement component 5 (C5) inhibitor. Both NGM-621 and ARC1905 zero in on the complement system because this pathway’s dysregulation is implicated in AMD progression.

Investigating cell replacement therapy

As for Luxa Bio, on May 24 the company announced it dosed its first patient in a Phase I/IIa trial (NCT04627428) investigating its dry AMD asset RPESC-RPE-4W. In an interview with Clinical Trials Arena, Stern says the company has rough plans on what a Phase IIb trial would look like, which could initiate in H2 next year or in 2024, pending Phase I/IIa data. The FDA will allow Phase IIb after one-year positive outcomes are available from Phase I/IIa, Stern adds.

Luxa Biotechnology co-founder Dr Jeffrey Stern

After determining the dose and assessing adverse effects in the ongoing trial, approximately 12 patients from the Phase I/IIa would be re-enrolled for Phase IIb, with the addition of 30–40 new participants, Stern notes. In the ongoing 18-participant study, half of the subjects will be legally blind with visual acuity of 20/200 to 20/400, with the other half having an intermediate range of vision loss, he says. Patients in the second group are willing to trade the risks involved with transplant in exchange of possibly improved vision, he explains.

Younger cells may offer better efficacy potential

RPESC-RPE-4W features allogeneic RPE stem cell (RPESC)-derived RPE cells (RPESC-RPE) taken from human cadaveric eyes. RPE derived from stem cells is intended to improve vision quality by stimulating regeneration and replacing damaged tissue.

While there are other trials also investigating cell replacement therapies, Luxa found that the maturity of the cell is vital. In preclinical animal studies, Stern and his co-founding partner Dr Sally Temple found that developmentally younger cells at four weeks of differentiation are more vision reparative than fully mature cells. As such, this approach is used with RPESC-RPE-4W.

Luxa Bio is seeking ways to improve how RPESC-RPE-4W is stored and transported. Stern says that the company is looking into frozen modifications to the fresh version of RPESC-RPE-4W, which is in the ongoing trial. With positive early Phase I/IIa data, a new protocol would be delivered to the FDA to potentially investigate the frozen version in the Phase I/IIa as an added investigation arm. The frozen version has shown in vitro efficacy signals and would offer logistic advantages.

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