New study affirms promise of anti-integrin drug for DME

Reviewed by Vicken Karageozian, MD

A new class of ophthalmic drug continues to show promise for treating patients with diabetic macular edema (DME).

This intravitreally injected therapy, ALG-1001 (Luminate, Allegro Ophthalmics) is an anti-integrin peptide. The novel therapy showed promising results in monotherapy in the form of visual acuity gains and decreased central macular thickness when compared with injections of an anti-vascular endothelial growth factor (anti-VEGF) drug, bevacizumab (Avastin, Genentech).  

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One of the most important findings when Luminate was compared with bevacizumab in the DEL MAR Phase IIb/stage 1 clinical trial was that the number of injections of ALG-1001 needed to achieve similar visual results was half that needed with bevacizumab, thus decreasing the patient treatment burden.

Figure courtesy of Allegro OphthalmicsVicken Karageozian, MD, president and chief medical officer, described ALG-1001 as a small molecule that is 1% of the size of popular anti-VEGF drugs, such as bevacizumab, ranibizumab (Lucentis, Genentech), and aflibercept (Eylea, Regeneron Pharmaceuticals) used to treat vitreoretinal diseases.

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“(ALG-1001) is a synthetic molecule that mimics a natural master key that blocks the cell-to-cell and cell-to-extracellular matrix communications for angiogenesis,” Dr. Karageozian explained. “It is the first formulation in retina for retinal angiogenesis that does not work on the signaling pathway directly–that is, it does not turn the signals off, but rather interferes with the communications for construction.”  

Phase IIb/stage 1 study

A total of 136 patients with DME were enrolled in this controlled, double-masked, multicenter study in 32 sites across the United States. The study protocol evaluated the efficacy of 3 doses of ALG-1001 (1.0, 2.0, and 3.0 mg) in 3 intravitreal injections. The results were compared with those of 1.25 mg of bevacizumab administered in 6 injections.

The primary endpoints were 12 weeks off of ALG-1001 treatment and the efficacy of the drug as demonstrated by the improvements in the mean best-corrected visual acuity (BCVA) and those on optical coherence tomography (OCT). The primary endpoint of the DEL MAR Phase II study was to demonstrate the non-inferiority of ALG-1001 to bevacizumab, which was defined as a difference of 3 or fewer letters in the mean change in the BCVA at 20 weeks after treatment.

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Dr. Karageozian reported that ALG-1001 met the primary end point. At the 20-week time point after baseline, the data showed that the mean gain in BCVA was 5.2 letters for patients treated with the 1.0 mg of ALG-1001 12 weeks off ALG-1001 loading compared to 7.0 letters for patients treated with the 1.25 mg of bevacizumab who were dosed every 4 weeks.

Figure courtesy of Allegro OphthalmicsThe secondary endpoint, i.e., non-inferiority to bevacizumab, was defined as a 30 µm or less difference in the mean change in the central macular thickness measured by OCT.

“At week 20, patients in the 1.0-mg (ALG-1001) arm showed a mean reduction of 77 µm 12 weeks off  (ALG-1001) loading versus 104 µm in the 1.25-mg bevacizumab arm dosed every 4 weeks,” Dr. Karageozian said. 

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The study results also indicated that ALG-1001 was well-tolerated with no drug toxicity or intraocular inflammation observed. “These safety results are consistent with previously conducted (ALG-1001) studies on human subjects where there were no reports of significant inflammation, no afferent pupillary defects, and no evidence of retinal tears or detachments,” he added.

ALG-1001 remains bound to the retina over an extended period of time, but when it does enter the systemic circulation, it breaks down almost immediately. Because of this, no systemic reactions have been observed.

“We had a hard time finding any evidence of the drug in the peripheral blood, even upon close examination,” Dr. Karageozian said.  

Future applications

The recent trend has been toward use of various anti-VEGF drugs in combination with other drugs to treat vitreoretinal formulations. That also seems possible with ALG-1001.

Dr. Karageozian explained that a combination of drugs used in animal models of age-related macular degeneration (AMD) and DME worked well when evaluated by Peter Campochiaro, MD, and colleagues at the Wilmer Eye Institute/Johns Hopkins University School of Medicine, Baltimore.

Allegro also is conducting a phase II/stage 2 study that is looking at the efficacy of administering bevacizumab and ALG-1001 concurrently, as well as beginning treatment with bevacizumab and switching to ALG-1001 in patients with DME. The results are expected in the second quarter of 2017.

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Another potential indication for ALG-1001 is for vitreolysis in posterior vitreous detachment and vitreomacular traction.

While this drug is intended to treat DME, it also will be applicable to wet AMD, Dr. Karageozian pointed out, and he touted the benefits of the 12-week increased durability in DME, increased safety, similar potency to anti-VEGF drugs, and a new mechanism of action with new treatment options. In addition, it is sufficiently potent to be used as monotherapy.

“The fact that this study met the primary end point means that for the first time in a long time, there is an entirely new class of drug that can stand on its own for vision and anatomy in DME and probably in wet AMD,” Dr. Karageozian outlined. “It is important to remember that while the anti-VEGF drugs are popular, only about 50% of the patients with DME achieve functional vision–that is vision that is sufficiently good for reading, driving, and working.

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“Considering that there are 5 million patients with DME and wet AMD in the United States, use of one category of drug to treat these patients is inadequate over time. (ALG-1001) will likely be used in the 50% of patients with less-than-perfect results, and then as combination and/or adjunctive therapy also,” Dr. Karageozian concluded.

Vicken Karageozian, MD

E: vkarageozian@allegroeye.com

Dr. Karageozian is an employee of Allegro Ophthalmics.