Article

The Looming Unmet Need in Diabetic Eye Care

Part 2: New approaches to therapy are working their way through the pipeline.

In a previous issue of Retinal Physician, I outlined how immense growth in the prevalence of diabetes is creating a daunting global health burden. To address the associated challenge of diabetic eye disease, retinal physicians will need treatment strategies beyond those available today. Many new treatment options are currently being developed, including novel anti-VEGF agents, new steroid delivery methods, combination drugs that target the angiopoietin pathway, and integrin peptide therapy.

ANTI-VEGF AGENTS

VEGF-A inhibition remains an active area of research in eye care. Two potential new therapies for diabetic eye disease in this category are abicipar pegol (Molecular Partners and Allergan) and RTH258 (Alcon). Both are small molecules, which means they may bind more efficiently to their targets to provide increased efficacy and duration of action. Their size may also make them more amenable to be used in a drug-delivery device.

Abicipar pegol is a DARPin drug. DARPins are a new class of potent, specific, versatile small-protein molecules developed at the University of Zurich in Switzerland. They are derived from natural ankyrin repeat proteins, which are binding proteins with diverse functions, such as cell signaling and receptor binding. It’s believed that their flexible architecture gives DARPins the potential to overcome some of the limitations of current therapeutic approaches to complex diseases. Abicipar pegol was recently compared with ranibizumab (Lucentis, Genentech) in a phase 2 trial involving 151 patients with DME.1 Abicipar 2 mg (Q8 weeks and Q12 weeks, following 3 monthly loading doses) demonstrated functional (best corrected visual acuity [BCVA]) and anatomical (central retinal thickness) effects comparable to monthly ranibizumab, with fewer injections over a 28-week period. Enrollment is under way for a phase 3 trial using an updated formulation of abicipar, and initial results are expected in 2018.

RTH258 is currently undergoing study as a treatment for wet AMD and will likely be studied for diabetic eye disease as well. RTH258 is a single-chain antibody fragment that inhibits all isoforms of VEGF-A. In the first-in-human study of RTH258,2 which involved 194 treatment-naïve wet AMD patients, the treatment demonstrated noninferiority to ranibizumab in mean change in central subfield thickness from baseline to month 1 in 4.5-mg and 6.0-mg dose groups. The median time to post-baseline therapy after baseline therapy was 60 days for the 4.5-mg group, 75 days for the 6.0-mg group, and 45 days for ranibizumab group. Changes in BCVA with RTH258 were comparable to those seen with ranibizumab.

Inhibition of other members of the VEGF family is also being explored. The pharmacokinetics and pharmacodynamics of intravitreal OPT-302 (Opthea), administered for 3 months with and without ranibizumab in patients with wet AMD, are currently being evaluated in humans. In a preclinical mouse model of wet AMD, OPT-302 was shown to reduce the development of wet AMD lesions and inhibit leakage of associated vessels to an extent comparable to aflibercept (Eylea; Regeneron).3,4 Furthermore, when the 2 agents were used together, an additive benefit was observed. OPT-302 also appears capable of reducing the expression of genes involved in blood vessel growth and inflammation. It blocks the activity of VEGF-C and VEGF-D, which promote angiogenesis and help to induce vascular permeability and are thought to play a role in mediating resistance to anti-VEGF-A therapies. Given what’s been learned so far about OPT-302, logically it would also be evaluated in diabetic eye disease.

NEW STEROID DELIVERY METHODS

Sustained-release devices such as the dexamethasone 0.7 mg intravitreal implant (Ozurdex; Allergan) and the fluocinolone acetonide 0.19 mg intravitreal implant (Iluvien; Alimera Sciences) have changed the way retinal physicians use steroids for DME, and new steroid delivery locations are a possibility in the future. Injection of a proprietary formulation of triamcinolone acetonide (Zuprata; Clearside Biomedical) into the suprachoroidal space is now being evaluated in a phase 1/2 study, the HULK trial, as monotherapy as well as concomitant with intravitreal aflibercept in patients with DME. In the TANZANITE trial, a previous phase 2 trial involving treatment-naïve patients with macular edema due to retinal vein occlusion, patients who received both intravitreal aflibercept and the suprachoroidally delivered steroid required fewer aflibercept retreatments and had better BCVA improvement than those who received aflibercept alone during the 3-month observation period.5 Drug delivery to the suprachoroidal space may be an effective way to target the therapeutically relevant ocular structures while limiting exposure to others.6

TARGETING THE VEGF AND ANGIOPOIETIN PATHWAYS TOGETHER

Targeting the VEGF pathway and the angiopoietin growth factor pathway at the same time is an approach gaining momentum to address not only wet AMD and DME but also potentially diabetic retinopathy (DR), which develops earlier in the disease process. Three strategies for accomplishing this are being investigated: administration of 2 separate agents at the same time, use of a bispecific monoclonal antibody, and use of a coformulation.

AKB-9778 (Aerpio Therapeutics), delivered subcutaneously, activates the TIE-2 transmembrane tyrosine kinase receptor, which is essential for vascular stability, as it inhibits permeability, blood retinal barrier breakdown, and inflammation. It does so regardless of the levels of TIE-2 agonists angiopoietin-1 and angiopoietin-2 (ang-2) that are present, meaning it may work independently of those, which may be clinically advantageous. In the phase 2 TIME-2 study, daily subcutaneous injections of AKB-9778 were administered with and without monthly intravitreal injections of ranibizumab for 3 months in patients with DR, with or without DME. The combination of AKB-9778 and ranibizumab provided a clinically significant benefit in reduction of central subfield thickness compared to ranibizumab alone. The percentage of patients who achieved an improvement of two or more steps on the diabetic retinopathy severity scale from baseline was highest in the ranibizumab plus AKB-9778 group compared with the ranibizumab alone group and the AKB-9778 alone group. Notably, AKB-9778 was also shown to have an effect on the fellow eye.

RG7716 (Roche) is an elegantly designed bispecific monoclonal antibody. An anti-VEGF-A arm and an anti-ang-2 arm are bound together by an Fc fragment in one molecule. The Fc fragment is modified to eliminate 2 binding sites, which results in lowered systemic concentration following intravitreal injection and a reduced potential for platelet activation, thus optimizing RG7716 for ocular use. In a phase 1 study,7 RG7716 improved BCVA and reduced central subfield thickness in patients with wet AMD, 20/40 to 20/400 BCVA, and persistent choroidal neovascularization despite 3 or more anti-VEGF treatments in the prior 6 months. A phase 2 trial in patients with wet AMD, AVENUE, and a phase 2 trial in patients with DME, BOULEVARD, are under way.

A coformulated single intravitreal injection consisting of the ang-2 antibody nesvacumab and aflibercept, REGN910-3 (Regeneron and Bayer), is currently in phase 2 studies for wet AMD and DME.

INTEGRIN PEPTIDE THERAPY

An integrin peptide therapy, Luminate (Allegro Ophthalmics), is currently being tested in a phase 2 clinical trial that enrolled patients with DME. Luminate targets integrin receptors with 2 mechanisms of action: antiangiogenesis and vitreolysis. Integrins are cell-to-cell adhesion molecules that are involved in cell signaling and regulation and construction of new and aberrant blood vessels. The phase 2 trial is comparing intravitreal injections of Luminate with current standard of care for patients with DME. Patients are randomized to 1 of 5 treatment groups that include 3 Luminate dose groups, a bevacizumab (Avastin, Genentech) group, and a focal laser photocoagulation group. In a phase 1 study,8 of 15 end-stage DME patients treated with Luminate experienced a 3-line to 5-line improvement in visual acuity with a corresponding improvement in macular anatomy as measured 3 months after treatment.8

ON THE RIGHT PATH

The hope for these innovative potential new therapies as they move through clinical trials is that they will be able to improve the care retinal physicians can provide to patients with diabetic eye disease by making treatment more sustainable. They may do this by harnessing synergies to make current treatments more effective, including in recalcitrant cases, reducing the frequency of treatment that is required to save vision, or in ways yet to be discovered. RP

REFERENCES

  1. Hassan TS. A multicenter, double masked phase 2 clinical trial evaluating abicipar pegol for diabetic macular edema. Presented at the annual meeting of the American Academy of Ophthalmology; October 15, 2016; Chicago.
  2. Holz FG, Dugel PU, Weissgerber G, et al. Single-chain antibody fragment VEGF inhibitor RTH258 for neovascular age-related macular degeneration: a randomized controlled study. Ophthalmology. 2016;123(5):1080-1089.
  3. Lashkari K, Ma J, Teague G, Arroyo JG. Expression of VEGF-C, VEGF-D and their cognate receptors in experimental and clinical choroidal neovascularisation. Poster presentation, annual meeting of the Association for Research in Vision and Ophthalmology; May 8, 2013; Seattle. http://iovs.arvojournals.org/article.aspx?articleid=2149913 .
  4. Lashkari K, Ma J, Teague G, Guo C, Baldwin ME. VEGF-C and VEGF-D blockade by VGX-300 inhibits choroidal neovascularization and leakage in a mouse model of wet AMD. Poster presented at the annual meeting of the Association for Research in Vision and Ophthalmology; May 6, 2014; Orlando, Florida. Available from: http://iovs.arvojournals.org/article.aspx?articleid=2267101
  5. Clearside Biomedical, Inc. announces positive preliminary phase 2 results in patients with macular edema associated with retinal vein occlusion [press release]. Alpharetta, GA: Clearside Biomedical, Inc. April 26, 2016. Available from: http://phx.corporate-ir.net/phoenix.zhtml?c=253669&p=irol-newsArticle&ID=2162115 .
  6. Edelhauser H, Patel S, Meschter C, Dean R, Powell K, Verhoeven R. Suprachoroidal microinjection delivers triamcinolone acetonide to therapeutically-relevant posterior ocular structures and limits exposure in the anterior segment. Invest Ophthalmol Vis Sci. 2013;54(15):5063. Available from: http://iovs.arvojournals.org/article.aspx?articleid=2149985 .
  7. Dugel P. A novel anti-VEGF/anti-angiopoietin2 bispecific monoclonal antibody for wet age-related macular degeneration and diabetic macular edema. Presented at: American Society of Retina Specialists annual meeting; August 10, 2016; San Francisco.
  8. Allegro Ophthalmics begins phase 2 clinical trial of Luminate (Alg-1001) for the treatment of diabetic macular edema [press release]. Chicago: Allegro Ophthalmics. May 4, 2015. Available from: http://www.allegroeye.com/press-release/allegro-ophthalmics-begins-phase-2-clinical-trial-of-luminate-alg-1001-for-the-treatment-of-diabetic-macular-edema/ .