Investigational drug Luminate targets integrin receptors

Take-home message: Anti-integrin therapy is a promising new approach in the treatment of vitreoretinal disease. The first drug in this class, Allegro Ophthalmics’ Luminate, is in Phase 2 clinical trials for several indications, including wet age-related macular degeneration, diabetic macular edema, non-proliferative diabetic retinopathy, and vitreomacular traction.

By Vicken Karageozian, MD, Special to Ophthalmology Times

Anti-integrin therapy is a promising new approach in the treatment of vitreoretinal disease. The first drug in this class, Allegro Ophthalmics’ Luminate, is in Phase 2 clinical trials for several indications, including wet age-related macular degeneration (AMD), diabetic macular edema (DME), non-proliferative diabetic retinopathy (NPDR), and vitreomacular traction (VMT). 

Thus far, Luminate has been shown to have potency comparable to that of anti-VEGF agents when used as monotherapy; unprecedented durability for three or more months off-treatment; and safety and efficacy in more than 180 treated patients to date. As clinical trials progress, we continue to learn more about its dual mechanism of action and the potential for anti-integrin therapy in clinical practice.

Why target integrins?

In the broadest sense, integrins are cell adhesion and cell signaling receptors. Located throughout the body, they control how cells communicate with each other and with the extracellular matrix (ECM). As one might expect, given their role in cell-to-cell interactions, integrin receptors are located on cell surfaces, but they also are capable of transmembrane regulation ‒ that is, sending instructions down into the cell itself ‒ which makes them a compelling therapeutic target. 

Each type of integrin receptor is named for its unique combination of alpha and beta subunits (Figure 1). We know of at least 27 types of integrin receptors, some of which have been implicated in systemic diseases as diverse as cancer, osteoporosis, and autoimmune conditions. In the eye, integrin receptors have been closely associated with choroidal and pre-retinal angiogenesis, vitreolysis, and ocular surface inflammation. 

For example, α_vβ₃ has been observed in choroidal neovascularization (CNV) associated with wet AMD.¹

Along with integrin α_vβ₅, it also has been observed in neovascularization associated with proliferative diabetic retinopathy (DR).¹ Integrin α₅β₁ is expressed in neovascular ocular tissue in wet AMD and DR, and targeting it effectively inhibits endothelial cell proliferation by multiple pathways.²

Finally, integrin α₃β₁ mediates the attachment of the vitreous to the retinal surface. Targeting it induces vitreous liquefaction and posterior vitreous detachment (PVD),³ which may be helpful for the release of VMT and treatment of patients with NPDR.

Scientists have understood the importance of integrin receptors for more than two decades. However, previous attempts to develop anti-integrin therapy relied on large molecular weight agents (such as monoclonal antibodies or aptamers) that targeted a single integrin receptor and generally had to be continuously administered intravenously, limiting their utility.

Luminate is a synthetic arginine-glycine-aspartic acid (RGD)-class oligopeptide that binds to multiple integrin receptor sites (α_vβ₃, α_vβ₅, α₅β_1, and α₃β₁) and affects multiple pathways to treat vitreoretinal disease. The novel science behind it was validated recently with the issuance of a U.S. patent covering its composition of matter and methods of use in the treatment of various ophthalmic disorders, neovascular conditions, and tumors.

Inhibiting angiogenesis

We know that vascular endothelial growth factor (VEGF) plays an important role in initiating the angiogenic cascade. When VEGF production is elevated, it signals the angiogenic pathway that more blood vessels are needed to provide more oxygen. By preventing VEGF-mediated leakage, anti-VEGF agents have become an important part of the standard of care for both AMD and DME. However, some patients don’t respond completely to anti-VEGF therapy. Among those who do, the necessity for frequent injections can become a burden. 

Targeting integrins instead of or in addition to VEGF offers the potential to treat these diseases more effectively. Integrins have effects that are both upstream and downstream of the VEGF pathways. For example, targeting integrins can prevent the proteolytic degradation of the ECM and tissue remodeling that is necessary for a new vascular sprout to penetrate the surrounding tissue, well before that blood vessel could begin to leak. Later in the cycle, integrins also mediate cell maturation and differentiation. By inhibiting the activity of all three integrin subtypes associated with angiogenesis, Luminate is able to inhibit further growth of abnormal blood vessels, turn off production of new blood vessels, and cause leakage from existing neovascularization to dry up.

In clinical trials thus far, human subjects with wet AMD or DME who received three monthly injections of Luminate as monotherapy experienced significant improvements in vision and central macular thickness that continued for three months off-treatment. Larger Phase II efficacy studies comparing Luminate to standard treatment are under way for DME and will soon begin for wet AMD.

Promoting vitreolysis

The vitreolytic mechanism of action for anti-integrin therapy also is very promising. 

As noted previously, integrin receptor α₃β₁ mediates the attachment of the vitreous to the retinal surface, as shown in the top right panel of Figure 2. When this receptor is competitively inhibited from attaching to the ECM (Figure 3), there is release of cellular adhesion. In the recently completed Phase 2 clinical trial, 65% of eyes treated with the 3.0-mg dose of Luminate achieved release of VMT or vitreomacular adhesion (VMA) at three months, compared to 10% of those in the control group (p=0.0129).

We also have seen in studies that anti-integrin therapy can induce vitreous liquefaction and overall detachment of the posterior face of the vitreous from the retina. In a hypoxic diabetic eye, there is a depot-like concentration of VEGF, platelet-derived growth factor (PDGF), and other angiogenic factors in the vitreous, right over the retina ‒ exactly where those angiogenic factors can do the most harm. Liquefying the vitreous and inducing a PVD (Figure 4) will lower the VEGF levels and prevent them from continuing to accumulate. Ono and colleagues found that PVD dramatically reduced the rate of progression from NPDR to proliferative DR over a three-year period, from 35%-40% without PVD to ≤5% in the presence of a PVD.⁴

Phase 2 clinical trials of Luminate in eyes with NPDR have just begun. This is a very promising indication, given that there are no other drugs approved for the induction of PVD.

It is rather unusual for a company to pursue multiple indications at once, but this is something Allegro Ophthalmics has undertaken in a very purposeful manner. With sufficient financial resources, extensive experience in ophthalmic drug development that collectively spans more than 100 years, and very good proof-of-concept data on all four indications, Allegro Ophthalmics plans to move forward with multiple “shots on goal” in the campaign to find additional and potentially more efficacious treatments for a wide range of vitreoretinal diseases.

References

• Friedlander M, Theesfeld C, Sugita M, Fruttinger M, Thomas M, Chang S, Cheresh D. Proc Natl Acad Sci USA. 1996 Sep 3;93(18):9764-9.

• Ramakrishnan V, et al. Exp Ther Oncol. 2006;5(4):273-86.

• Oliveira L, Meyer C, Kuman J, Tatbayashi M, Toth C, Wong F, Epsein D, McCuen B. Curr Eye Res. 2002 Dec;25(6):333-40.

• Ono R, Kakehashi A, Yamagami H, et al. Prospective assessment of proliferative diabetic retinopathy with observations of posterior vitreous detachment. Int Ophthalmol. 2005;26:15-19.

Vicken Karageozian, MD

P: 949/940-8130

E: vkarageozian@allegroeye.com

Dr. Karageozian is a partner at Clarity Eye Group in Huntington Beach, CA. For the past 21 years, he also has been involved in biotechnology and drug development, most recently as chief technology officer of Allegro Ophthalmics, the makers of Luminate.