Outlook for integrin peptide therapy

TAKE-HOME

ALG-1001 is the first of a new class of drugs, integrin peptide therapy, now going through clinical trials for patients with age-related macular degeneration, diabetic macular edema, and vitreomacular traction.

Dr. Kaiser

By Peter K. Kaiser, MD, Special to Ophthalmology Times

Cleveland-Therapies that target vascular endothelial growth factor (VEGF) have been tremendously important in the treatment of wet age-related macular degeneration (AMD) and diabetic macular edema (DME). Yet, there are still significant gaps in ophthalmology’s ability to treat these diseases.

For patients with wet AMD, current anti-VEGF treatments very quickly reduce leakage and improve vision, with dramatic improvements compared with baseline. An ongoing challenge, however, is that many patients don’t respond to anti-VEGF therapy and for those who do, maintaining the gains over time requires frequent injections. The AURA study, an observational study in several European and South American countries, has recently made this all too clear.¹

In countries where subjects had frequent injections of ranibizumab, they achieved and maintained an 8- to 9-letter gain in visual acuity, similar to U.S. clinical trial results. In countries where insurance issues or practice patterns limited the number of injections per year, the subjects had no gain in vision or even a mean loss in visual acuity.

The reality is that it is very difficult to apply anti-VEGF therapy as frequently as needed. New or complementary therapies to extend the duration of effect are needed. Agents that treat angiogenesis via an entirely different pathway from VEGF may hold the key to increasing efficacy and reducing the treatment burden.

A multipronged approach

Currently approved therapies work by blocking VEGF in the extracellular space, thereby preventing VEGF-mediated leakage. However, the underlying choroidal neovascularization (CNV) persists, ready to leak again when treatment is stopped.

ALG-1001 (Allegro Ophthalmics) is the first of a new class of drugs, integrin peptide therapy, now going through clinical trials.

Integrins are a family of proteins that regulate attachments among cells and between cells and their surrounding tissues. Integrin receptors are located throughout the body, including on endothelial cells. By inhibiting integrin-mediated processes in the angiogenesis cycle, such as endothelial cell migration, proliferation, differentiation and maturation, studies have shown that ALG-1001 is able not only to dry up leakage from existing neovascularization, but also to inhibit growth of abnormal blood vessels and turn off production of new blood vessels.

In contrast to previous attempts to develop integrin therapies with monoclonal antibodies or aptamers, ALG-1001 is an integrin antagonist that blocks all the integrin α-β combinations rather than specifically targeting one particular subunit or subunit combination. Nonspecific agents can be problematic if they block desirable cell interactions.

So far, however, ALG-1001 appears to be working only on neovascular tissue, with no off-target effects in either animal models or human studies.

AMD study results

In the ALG-1001 phase Ib/IIa monotherapy trials for wet AMD, which were primarily designed to test safety, we also saw very good efficacy, even in patients who had already had multiple previous anti-VEGF injections.

Subjects (n = 22) had three monthly injections of ALG-1001 as monotherapy following a minimum 45-day washout period from any previous AMD therapy including anti-VEGF agents, then were observed for 4 more months off-treatment from either ALG-1001 or any other intervention. Peak average improvement in vision with a 3.2-mg dose was +5.2 letters two months off-treatment, with a 30% mean improvement in central macular thickness on OCT. The gains were maintained for four months off-treatment, and as long as five months off-treatment in some subjects (Figure 1).

While preliminary, this duration of effect is not something we typically see with currently approved treatments. The OCT evidence is also very promising with prolonged decreases in retinal thickness being seen. Analysis of the fluorescein angiography results is pending.

A larger, phase IIb efficacy trial was cleared in late 2013, and includes a monotherapy arm, as well as a combination therapy arm with anti-VEGF. Not only is there a sound scientific rationale for combining two agents with different mechanisms of action, but there is also evidence from animal studies that the combination of ALG-1001 with anti-VEGF agents may achieve greater reduction in CNV size than either one alone.

Treating diabetic eye disease

Diabetic eye disease poses even greater challenges for our current treatment options, none of which truly addresses the underlying damage to the retinal vasculature. Instead, laser and intravitreal anti-VEGF or steroid treatments target the leakage that results from that damage. Unfortunately, this means it is not at all unusual to have patients in our practices with persistent edema even while on therapy. In these patients, integrin antagonism may offer a longer-lasting and perhaps more efficacious approach.

During a phase I safety study, 15 subjects with persistent DME received three monthly injections of 2.0-mg ALG-1001 following a 90-day washout period from previous therapy, with an additional three months of off-treatment observation. None of the 15 patients lost any vision during the trial, even three months off-treatment. Eight of the 15 had visual acuity improvements sufficient to return them to functional vision, which was very satisfying (Figure 2).

A corresponding improvement in central macular thickness was also maintained for the duration of the study. Most importantly the safety was excellent. A Phase 1b/2a placebo-controlled DME trial is also underway to confirm the primary safety and efficacy results of ALG-1001 in combination with anti-VEGF therapy.

Another promising finding in this study was a secondary endpoint showing that six of 11 eyes with no or partial posterior vitreous detachment (PVD) at baseline developed a total PVD within 90 days of beginning therapy. This wasn’t entirely unexpected, given that ALG-1001 binds to integrin α₃β₁ receptor sites at the vitreoretinal interface, facilitating the release of cellular adhesion between the vitreous and the retina. But it is very exciting because we don’t currently have good options for diabetic patients with vitreomacular adhesion (VMA) or traction (VMT).

Ocriplasmin (Jetrea, Thrombogenics) has been successful in treating non-diabetic eyes with VMT but subjects with active diabetic retinopathy were specifically excluded from the ocriplasmin clinical trials. Even among subjects with diabetes with no ocular manifestations, very few achieved VMT release in the ocriplasmin trials; however, it is not known if this was due to the small sample size since the study was not powered to evaluate efficacy in this subgroup.

Clinically and surgically, we know the vitreous in diabetic eyes behaves very differently than in non-diabetics. There are more glial cells and the vitreous forms a stronger attachment, increasing the potential for posterior hyloidal traction (Fig 3).

By inducing PVD and liquifying the vitreous in these eyes, we may be able to protect them against a number of complications, including hemorrhage, macular edema, and traction retinal detachment. This could further improve outcomes and preserve vision in patients with diabetes. A phase II study is currently enrolling patients to evaluate the efficacy of ALG-1001 in resolving VMT.

Within a few years, we hope to learn whether ALG-1001 will work in larger populations of patients with age-related macular degeneration, diabetic macular edema, and vitreomacular traction. Throughout the phase II and III clinical trials, we’ll be looking for confirmation of safety and overall efficacy, as well as more data on the duration of effect, ideal frequency of injections, and any synergies with current treatments. More research is needed but, based on the early data, I am optimistic that integrin peptide therapy will play an important role in our armamentarium in the near future.

Peter K. Kaiser, MD, is a staff member of the vitreoretinal faculty of the Cole Eye Institute in the Department of Ophthalmology at Cleveland Clinic and Founding Director of the Digital Optical Coherence Tomography Reading Center (DOCTR) at the Cole Eye Institute. He serves on the Scientific Advisory Board for Allegro. Readers may contact him at pkkaiser@gmail.com or 216/444-6702.

Reference

1.     Hoyng CB. Retrospective analysis of the real-world utilization of ranibizumab in wAMD. European Society of Ophthalmology, June 2013, Copenhagen.

Subscribe to Ophthalmology Times to receive the latest clinical news and updates for ophthalmologists.