Exonate’s pipeline of novel small molecule inhibitors (“SPHINXes”) is designed to address areas of significant unmet medical need. The founders have identified several mRNA splicing and angiogenesis-related disease indications for which the company’s compounds promise improved selectivity, efficacy and safety. Exonate’s initial focus is to develop treatments for wet Age-Related Macular Degeneration (wet AMD), the leading cause of blindness in people over 65.
Working with Professor Jonathan Morris at the University of New South Wales, Exonate’s founders have discovered compounds that inhibit a protein kinase called SRPK1, which is a key regulator of mRNA splicing – the production of different forms of proteins from the same template (mRNA). During angiogenesis-related diseases, SRPK1 promotes production of a pathological form of the protein vascular endothelial growth factor (VEGF) that drives angiogenesis and disease progression.
VEGF is a validated therapeutic target, and anti-VEGF inhibitors are the current standard of care in wet AMD and a mainstay of cancer therapy across multiple tumour types. However, current therapies are expensive to manufacture and administer, and are associated with limited efficacy, resistance, off-target effects and toxicity. In pre-clinical studies of wet AMD and cancer, inhibition of SRPK1 reduces pathological VEGF, angiogenesis and disease progression without inhibiting non-pathological, protective forms of VEGF, and so has the potential to offer safer, more efficacious therapies.
Wet AMD affects more than 30 million people worldwide and over 200,000 in the UK alone, with disease prevalence expected to increase more than 50% by 2020 in an ageing population. These patients, if untreated, are likely to lose sight in the affected eye within 24 months of onset. The introduction of the VEGF-inhibitor Lucentis® in 2006 resulted in anti-angiogenic therapy becoming the standard of care in wet AMD, with 40% of patients responding with improved vision. However, treatment with Lucentis® is expensive and must be injected directly into the eye once a month.
Exonate’s molecules act via a novel mechanism of action to inhibit pathological blood vessel growth underlying progression to blindness. In wet AMD, mRNA splicing increases production of pathological forms of VEGF. By specifically targeting the protein that regulates this pathological mRNA splicing, Exonate’s small molecule inhibitors reduce formation of pathological VEGF without inhibiting beneficial, non-pathological VEGF. Exonate’s molecules are therefore more specific and may be associated with fewer off-target effects and toxicity and improved safety profiles.
The company has developed formulations that can be administered as topical eye drops, offering substantially improved quality of life for patients, and much lower cost to administer, compared to the current standard of monthly injections into the eye. Monthly injections directly into the eye are unpleasant, time-consuming, expensive and associated with increased risk of infection. Removing these problems by generating simple eye drops for self-administration promises to reduce healthcare costs and improve patient quality of life.
Exonate’s lead compound shows excellent promise in pre-clinical testing, and is currently under development in further pre-clinical trials to enable testing in clinical trials. Although at an early stage, the promise of this programme is attracting the attention of potential pharmaceutical partners.
Angiogenesis- and mRNA splicing-related diseases constitute a large and growing market opportunity. Within Exonate’s first therapeutic target area of ophthalmology, wet AMD alone – the most prevalent form of angiogenic eye disease – constituted a ~$3 billion market in 2012, affecting more than 16 million people in the U.S., with disease prevalence expected to increase more than 50% by 2020. Current therapy requires intraocular injection of large molecules, so the market for Exonate’s molecules as topical eye drop administration is compelling. More broadly, VEGF as a target expands the market to include cancer, diabetes, chronic pain, neurodegeneration, renal disease, arthritis and many other major pathologies.