Tie-2/Angiopoietin pathway modulation as a therapeutic strategy for retinal disease

ABSTRACT

Introduction: The Tie-2/Angiopoietin pathway is a therapeutic target for the treatment of neovascular age-related macular degeneration (nAMD) and diabetic macular edema (DME). Activation of Tie-2 receptor via Ang-1 maintains vascular stability to limit exudation. Ang-2, a competitive antagonist to Ang-1, and VE-PTP, an endothelial-specific phosphatase, interfere with the Tie-2-Ang-1 axis, resulting in vascular leakage.

Areas covered: Faricimab, a bispecific antibody that inhibits VEGF-A and Ang-2, is in phase 3 trials for nAMD and DME. Nesvacumab is an Ang-2 inhibitor; when coformulated with aflibercept, it failed to show benefit over aflibercept monotherapy in achieving visual gains in phase 2 studies of nAMD and DME. ARP-1536 is an intravitreally administered VE-PTP inhibitor undergoing preclinical studies. AKB-9778 is a subcutaneously administered VE-PTP inhibitor that, when combined with monthly ranibizumab, reduced DME more effectively than ranibizumab monotherapy in a phase 2 study. AKB-9778 monotherapy did not reduce diabetic retinopathy severity score compared to placebo. AXT107, currently in the preclinical phase, promotes conversion of Ang-2 into a Tie-2 agonist and blocks signaling through VEGFR2 and other receptor tyrosine-kinases.

Expert opinion: Tie-2/Angiopoietin pathway modulators show promise to reduce treatment burden and improve visual outcomes in nAMD and DME, with potential to treat cases refractory to current treatment modalities.

KEYWORDS:

• Age-related macular degeneration
• angiopoietin
• AKB-9778
• ARP-1536
• AXT107
• diabetic macular edema
• faricimab
• nesvacumab
• Tie-2 receptor
• vascular endothelial growth factor

Article highlights

• Despite impressive advancements in treatment of neovascular age-related macular degeneration and diabetic retinopathy over the past two decades with anti-vascular endothelial growth factor (anti-VEGF-A) therapy, there is great need to reduce the treatment burden from frequent injections and to improve visual outcomes.

• While dual targeting of Ang-2 and VEGF via a coformulation of nesvacumab with aflibercept did not show sufficiently promising results in Phase 2 nAMD trials, Faricimab, a bispecific antibody targeting both VEGF-A and Ang-2, has advanced to phase 3 trials for nAMD and DME.

• Targeting of VE-PTP may offer an opportunity to explore angiopoietin-independent pathways. Despite early signs of clinical effectiveness with subcutaneously administered small molecule (AKB-9778), no clinical path-forward is revealed at this time. Local ocular delivery of a VEPTP-targeted antibody approach (ARP-1536) is currently under investigation.

• AXT107 offers a unique mechanism that promotes conversion of Ang-2 into a Tie 2 agonist, while also blocking signaling through VEGFR2. Ocular tolerability, safety, and efficacy of gel-based sustained release formulation remains to be proven.

• Despite the promising early clinical results of Ang/Tie-2 modulators, it is unclear how this new targeted pathway will fit into the grand scheme of DME and nAMD treatment, given the many other investigative treatments on the verge of breakthrough for the same indications.

This box summarizes key points contained in the article.

Declaration of interest

R Hussain has served on the Advisory Board for Alimera Sciences. V Kansara is employed by Clearside Biomedical and was previously employed by Novartis and Merck. TA Ciulla has been previously employed with Ophthotech Corporation and Spark Therapeutics. He currently has an employment relationship with Clearside Biomedical Inc. A Harris receives remuneration from CIPLA, AdOM, and Shire for serving as a consultant. He holds an ownership interest in AdOM and Oxymap. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

Reviewer disclosures

One peer reviewer has received an honorarium for consultancy and lecture fees from Bayer, Genentech, Novartis, and Roche. Peer reviewers on this manuscript have no other relevant financial or other relationships to disclose.

Additional information

Funding

This paper was not funded.