Transforming the Treatment of Ocular Diseases and Cancer with Peptide Drugs

AsclepiX Therapeutics’ discovery platform has the potential to uncover peptides that can help restore balance to dysfunctional biochemical pathways involved in many different disease spaces.

The Importance of Homeostasis

Homeostasis refers to the ability to seek and maintain a condition of equilibrium or stability. For living things, maintaining homeostasis is critical for survival. Angiogenesis, also referred to as neovascularization, is one such tightly regulated, homeostatic process that occurs very rarely under normal physiological conditions, such as wound healing. 

The occurrence of uncontrolled neovascularization correlates with several serious angiogenic diseases characterized by the aberrant and unrestricted growth of new microvessels that often exhibit “leakiness” of blood and fluid.

Normally, the body uses self-regulating mechanisms to restore homeostasis and health, such as extracellular proteolysis and the release of biologically active peptides from the basement membrane during wound healing. The basement membrane comprises many structural proteins, including various types of collagen. The breakdown products of these structural proteins are peptides that function to maintain homeostasis, turning off and thus reining in excessive neovascularization, inflammation, and scar formation.

Bioinformatics Beginnings

AsclepiX Therapeutics, named after the ancient Greek god of medicine, was founded in 2011 to leverage new computational methods developed by Johns Hopkins researchers Aleksander S. Popel and Jordan J. Green. The company has since evolved with a focus on identifying therapeutic peptides. 

Popel and Green’s proprietary computational biology method enables the discovery of antiangiogenic homeostatic peptide sequences in the human proteome. By mining the human proteome for peptide sequences — shown to have antiangiogenic properties — and applying powerful bioinformatics tools, we discovered hundreds of novel antiangiogenic peptides in cryptic regions of nine different classes of proteins, including structural proteins, antiangiogenic proteins, proangiogenic proteins, chemokines, metalloproteases, and growth hormones.

Followed by Rational Drug Design

The multiple families of peptides identified using this computational approach are potent regulators of vascular homeostasis. The specific antiangiogenic properties of peptides from each class of protein were confirmed using endothelial cell proliferation and migration assays in vitro. Many of the most potent peptides in these in vitro assays also potently inhibited neovascularization in ocular models and inhibited tumor growth in multiple tumor types in mice. 

The receptors and mechanisms of action for the most promising candidates were identified and characterized so that their in vitro and in vivo activities could be studied. Our rational drug design involved the modification of the sequences of these leading peptides to make them more drug-like using structure–activity relationship (SAR) studies. Our clinical candidates are thus derived from the originally identified peptides and work through naturally existing, highly evolved mechanisms of homeostasis.

Within five to 10 years, we aim to make AsclepiX a leader in the ophthalmology space, and soon thereafter, establish leadership in the oncology field.

Lead Candidate Targets Ocular Diseases

In ophthalmology, we are initially focused on three of the leading causes of blindness in adults: diabetic macular edema (DME), neovascular (wet) age-related macular degeneration (wet AMD), and macular edema following retinal vein occlusion (RVO). 

To date, anti–vascular endothelial growth factor (VEGF) treatment has been the gold standard for treating retinal disease; however, many patients do not have a complete and lasting response with currently approved therapies. In patients who do respond, the duration of action of these treatments is short, requiring recurring and frequent intravitreal injections — as often as monthly. There is an unmet need for efficacious medicines that reduce the treatment burden for patients and ophthalmologists.

While gene and cell therapies have shown promise, there remain questions about their durability and safety, particularly for retinal diseases. A disruptive treatment that is known to be durable, safe, and easy to administer is still needed. Our lead candidate AXT107 meets these criteria.

A synthetic 20-mer collagen IV–derived peptide, AXT107 inhibits the activity of VEGF receptor 2 and activates Tie2, the other clinically validated pathway implicated in increasing vascular leakage and neovascularization in ocular diseases. AXT107 thus has a unique mechanism of action that leads to efficacy along two critical disease pathways to potentially provide a distinct and more efficacious therapeutic benefit than the currently available standard of care. 

In addition, AXT107 has unique properties that allow prolonged efficacy and safety with a single injection; upon injection into the vitreous, it self-assembles into a small gel-like depot, slowly releasing active levels of the peptide over several months without obstructing vision or interfering with the visual axis. AXT107 has demonstrated excellent safety in animal and toxicology studies for 15 months and efficacy in 10 different animal models of retinal disease, exhibiting superior performance to currently approved therapies in preventing and even reversing progressive pathologic changes in the retina and with the potential for just one injection per year.

AsclepiX will be filing an Investigational New Drug (IND) application with the U.S. Food and Drug Administration toward the end of 2020, and we anticipate initiating three phase I dose-escalation studies in DME, wet AMD, and RVO in the United States shortly thereafter. Global phase II and III studies will then follow.  

In the future, we believe that AXT107 may also become a groundbreaking new treatment for diabetic retinopathy (DR), one of the leading causes of blindness. Many patients develop DR in their teens and thus must receive frequent injections for decades. AXT107 has the potential to provide dramatic benefits in terms of vision gains and reduced treatment burden for these patients.

Other Peptide Candidates for Oncology

While our current focus is on advancing AXT107, AsclepiX has a diverse pipeline of peptide candidates targeting cancer indications. These treatments activate antitumor immunity, inhibit metastasis, and enhance efficacy in combination with immunotherapy and chemotherapy. 

AXT201 is a 20-mer collagen IV–derived peptide being developed to treat solid tumors. On its own, AXT201 has demonstrated potent tumor growth inhibition in aggressive mouse tumor models of triple-negative breast cancer (TNBC), targeting the tumor vascular and immune microenvironment. When combined with current standards of care, such as chemotherapy or immunotherapy, AXT201 can improve their delivery and efficacy.

AXT301 is a 24-mer CXC chemokine–derived peptide that inhibits tumor growth in orthotopic TNBC and glioma models. AXT501 is a 14-mer somatotropin-derived peptide that inhibits tumor growth in orthotopic TNBC models.

Building the Foundations

AsclepiX is a pioneer in innovation from a scientific excellence standpoint, and the validity of our approach is reflected in the rapid growth of the company and successful fundraising. We recently completed a $35 million Series A financing round.

We have also established a relationship with a contract development and manufacturing organization with expertise in peptides that has the ability to support our projects from preclinical through commercialization, ensuring quality and security of our supply chain.

Integrated Approaches Essential

Within five to 10 years, we aim to make AsclepiX a leader in the ophthalmology space, and soon thereafter, establish leadership in the oncology field. We believe that our integrated approach to drug discovery leveraging rapid advances in technology and increasing volumes of data will provide us with a greater understanding of diseases and their associated biological networks.

With further progress in computational methodologies and in vitro and in vivo disease models, we will continually improve our ability to identify therapeutic targets in retinal disease and oncology with the greatest potential for efficacy in clinical trials. We also hope to see clinical trials married with real-time data and conducted in real-life settings so they provide better representations of patient responses in the real world. 

Theresa Heah, M.D.

Theresa Heah, M.D., MBA is the Chief Medical Officer (CMO) and EVP Operations at AsclepiX Therapeutics. Prior to joining AsclepiX, Dr. Heah served as CMO at Applied Genetic Technologies Corporation (AGTC). Before AGTC, Dr. Heah was Vice President at Aerie Pharmaceuticals, where she was responsible for the development, approval and launches of Rhopressa® and Rocklatan®. Prior to Aerie, Dr. Heah served as Director, Senior Global Medical Affairs leading worldwide launch of EYLEA® followed by the role of Global Strategic Marketing Director EYLEA at Bayer.