With Integrins, Necessity Really is the Mother of all Invention

With Integrins, Necessity Really Is the Mother of all Invention

Stopping growth factors that create damage in the eye has proven lucrative. Lucentis (ranibizumab, Roche/Genentech) achieved sales of $1.8 billion in 2016 outside the US alone, and $1.46 billion within the US. Making surgical treatments safer (as the minimally invasive glaucoma surgery [MIGS] devices do) has also proven lucrative – the MIGS market is set to grow at a 47% CAGR between 2017 and 2022. The first device approved (Glaukos’ iStent) achieved revenue of $71 million in its second full year of commercialization.

Integrins gain traction

Now a newer category of drugs may follow the same pattern. Integrins are known to mediate cell functions and to activate intracellular pathways that control angiogenesis, inflammation, and cell survival. To date, 27 distinct integrin heterodimers have been described, predominantly in the alpha-subunits. They’ve been used successfully for years in treating various cancers – numerous publications exist on their effect in malignant melanoma – and are showing promise in the treatment of autoimmune disorders such as Crohn’s disease and colitis. Integrins are considered unique among the transmembrane receptors because they signal bidirectionally. Shire’s lifitegrast (Xiidra) was the first integrin antagonist approved for use in the eye, but others are coming.

[As an aside, Shire is also working on a new integrin antagonist for irritable bowel disease. In this case, SHP647 was acquired from Pfizer in 2016 and is the only anti-integrin directly targeting MAdCAM-1; Shire hopes the compound proves to be a more tolerable and effective treatment for IBD than anti-tumor necrosis factors have been.]

Luminate shows promise

Allegro Ophthalmics’ Luminate targets integrin receptors involved in both angiogenesis and inflammation. Three of the known integrin subtypes – αvβ3, α5β1, and αvβ5 – are expressed in diabetic retinopathy and wet macular degeneration.

In the DEL MAR Phase IIb Stage 2 results reported last month at the American Society of Retina Specialists meeting, Luminate met its primary endpoint – noninferiority to bevacizumab (Avastin, Roche/Genentech) in treatment of diabetic macular edema (DME). The Luminate sequential therapy group gained a mean of 7.1 letters in BCVA versus 6.7 letters gained in the Avastin-only arm. Those in the sequential therapy arm had four injections over 20 weeks: a loading dose of Avastin and three injections of Luminate at weeks one, four, and eight, and then 12 weeks off. The Avastin-only arm received monthly injections – five in all – over 20 weeks.

At their simplest, integrins act like sensors on a cell and control how those cells communicate to one another, says Vicken Karageozian, MD, president and CMO of Allegro. Luminate binds to the retinal pigment epithelium and “breaks the angiogenesis cycle because it basically tells cells to stop making the growth factor and to stop the inflammatory process.” While the anti-VEGFs “clean out” these growth factors, Luminate essentially eliminates the root source causing this damage and returns the cells to homeostasis.

Given what is known about the mechanism of action, Dr. Karageozian believes (at least initially) Luminate will likely be positioned as an adjuvant to anti-VEGF therapies before converting to a maintenance monotherapy. Allegro continues to investigate using Luminate in conjunction with anti-VEGF and, he says, “We’re very optimistic about that.”

Integrin candidate for glaucoma

Also developing anti-integrin therapy is Clanotech, whose α5β1 has been shown to have anti-angiogenic, antifibrotic, and anti-inflammatory properties. The company has said its product “offers a safe and efficacious profile in assisting glaucoma surgery techniques avoiding intra- and postoperative problems” encountered with the use of antimetabolites. Clanotech also believes its antagonist has potential to be an adjuvant to anti-VEGF therapies in neovascular age-related macular degeneration (AMD).

In Clanotech’s case, the company estimates the glaucoma surgery market may reach $1 billion by 2025, and its product will likely be recognized as an orphan drug.

While it’s too early to gauge the impact integrin antagonists will have on the retina market, it is clear that interest in novel ophthalmic treatments continues to grow.