Integrin Peptide Therapy
While anti-VEGF agents target the signaling for the creation of new blood vessels, Allegro’s Luminate® interferes with the construction and proliferation of new blood vessels. Luminate®, a first-in-class integrin peptide therapy, treats vitreoretinal diseases by utilizing two mechanisms of action (anti-angiogenesis and vitreolysis). As shown in clinical studies to date, Luminate® effectively regresses and inhibits new blood vessel formation, as well as reduces vascular leakage to maintain and restore vision, while significantly reducing the current burden of intravitreal injections.
The unique mechanisms of action in conjunction with the potential for reducing the burden of repeated intravitreal injections from every four to eight weeks to quarterly or even less frequent means that introducing Luminate® has the potential to provide additional benefits to patients over the current standard of care. Luminate® also allows for the potential benefits to be recognized by those patients who might not respond to the current standard of care or who do respond but whose vision does not return to a level of excellent vision.
Ophthalmic pre-clinical safety studies of Luminate® in rabbits and mice with both a single intravitreal injection as well as repeated multiple intravitreal injections have shown excellent safety and efficacy profiles. In addition to being well-tolerated in animals at doses significantly higher than the target human dose, animal studies have shown that Luminate® produces rapid, complete liquefaction of the rabbit vitreous and induces posterior vitreous detachment (PVD) within one to two days with no apparent toxicity or immunogenic side effects.
Additionally, in multiple animal model studies with Dr. Peter Campochiaro at Johns Hopkins University, Luminate® has demonstrated with statistical significance to regress neovascularization, inhibit the development of new aberrant blood vessels and reduce vascular permeability. Dr. Campochiaro’s studies also showed that a single intravitreal injection of Luminate® in a mouse model that over-expresses human vascular endothelial growth factor (VEGF) was comparable in efficacy to ranibizumab (Lucentis®). Similar cellular potency and anti-angiogenic activity was demonstrated when Luminate® was compared to aflibercept (Eylea®) in Dr. Campochiaro’s CNV mouse model (replicating AMD). However, Luminate® was four times more anti-angiogenic in Dr. Campochiaro’s ROP mouse model vs. Eylea® (replicating diabetic retinopathy).
Clinical Development Progress
Allegro’s current clinical development platform includes Phase II studies in multiple indications. Allegro is performing its current studies under its US IND application submitted in 2013. Below is a summary of clinical studies completed and in progress.
Phase I Diabetic Macular Edema (DME) Study [Completed]
The results of animal and early-stage human clinical studies of Luminate® have been very encouraging. There is no evidence of toxicity or safety concerns thus far. In phase I/II studies, Luminate® has demonstrated efficacy in a significant percentage of the limited number of patients in whom it has been tested. More intriguingly, a durable effect has been observed in patients who benefit from therapy. Improvements in vision and central macular thickness (CMT) have lasted several months beyond the last injection of the drug.
Allegro completed its Phase I Human Safety Study in patients with chronic advanced centrally-involved DME. Patients received three monthly intravitreal injections of Luminate®. These patients were then followed for an additional three months off-treatment. No study subjects experienced serious or significant adverse events. While this study was foremost a safety study, efficacy data show that 8 of 15 (53%) patients improved three to five lines on the eye chart, 50% of whom improved from legally blind to functional vision in the 20/40 to 20/60 range. Also, 8 of 15 (53%) patients experienced a 30% to 80% reduction in central macular thickness – an important factor impacting vision. These results were achieved despite the fact that these patients were in an advanced-stage of diabetic retinopathy, several failed to respond to repeated anti-VEGF treatment, and some had early proliferative diabetic retinopathy.
Additionally, this first human study showed efficacy of Luminate® in inducing a PVD – a positive outcome for altering the natural history of disease progression. Six of 11 (54%) subjects that entered the study without a total PVD developed a total PVD during the study
Phase Ib/IIa Wet Age-Related Macular Degeneration (AMD) Study [Completed]
In this six-month monotherapy study, the key criteria for trial inclusion included a baseline best-corrected visual acuity (BCVA) between 20/50 and 20/320, CNV due to AMD, and patients could not have received prior treatment with anti-VEGF treatment within 45 days of enrollment. The 22 participants enrolled in the trial were a combination of treatment naïve and previously treated. Luminate® was safe and well-tolerated, and a trend of treatment effect was seen to last more than four months off-treatment. There were significant improvements in visual acuity and CMT in the 3.2-mg dose group that held in most patients with a mean BCVA improvement of +4 ETDRS letters four months off-treatment with the improvement corresponding to nearly complete resolution of choroidal neovascularization (CNV) and sub-retinal fluid.
Phase IIb Vitreomacular Adhesion (VMA) and Vitreomacular Traction (VMT) Study [Completed]
Allegro presented topline results of the Phase IIb clinical trial evaluating the safety and efficacy of Luminate® in patients with VMA and VMT. The study met its primary endpoint with 65 percent of eyes treated with the 3.2 mg dose of Luminate® achieving release of VMT or VMA by Day 90 (end of study), compared to 9.7 percent of those in the placebo control group (balanced salt solution) (p=0.0129).
This prospective, randomized double-masked trial, which evaluated 106 study subjects and included three Luminate® groups (2.0 mg, 2.5 mg, or 3.2 mg) and a balanced salt solution (BSS) placebo group, also found that Luminate® was well-tolerated with no drug-related toxicity or intraocular inflammation noted with repeated intravitreal injections. These safety results are consistent with previously conducted Luminate® studies on human subjects where there were no rod or cone photoreceptor dysfunction on full-field electroretinogram testing, no afferent pupillary defects, and no evidence of retinal tears or detachments.
Phase IIb DME (DEL MAR) Study [On-going]
Allegro commenced a Phase IIb human clinical study that evaluates the safety and efficacy of Luminate® as compared to bevacizumab and focal laser photocoagulation in patients with DME. This double masked, placebo-controlled, randomized, six-month study builds upon human and animal safety and efficacy data generated to date for Luminate®. The trial is anticipated to close by end-of-year 2015 with first data read-out in the summer of 2016.
Phase IIb PVD (PACIFIC) Study [On-going]
Allegro began enrolling patients in a Phase IIb clinical study that will evaluate the safety and efficacy of Luminate® in inducing PVD in patients with non-proliferative diabetic retinopathy (NPDR). In this randomized, double-masked, placebo-controlled, multi-center, dose-ranging three-month trial, patients will be randomized to one of four treatment groups that include three Luminate® groups (1.0 mg, 2.0 mg, or 3.0 mg) and a placebo group. Topline results are anticipated in the summer of 2016.
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