With numerous players chasing the lucrative nAMD and diabetic retinopathy markets, PYC’s choice of indications for the second drug in its antisense pipeline could be seen as a bold move, one that is likely to attract wider attention.
Current approved therapies and most of those in development for these indications work by inhibiting VEGF-A. The most common goal of new entrants to the space is to extend the duration between treatment.
Another company in which I’m invested, Opthea, is seeking to improve on the efficacy of current VEGF-A inhibitors. Co-administered with a VEGF-A inhibitor, Opthea’s drug, OPT-302, also inhibits VEGF-C/D (which become elevated following VEGF-A inhibition) to provide a more complete suppression of the VEGF/VEGFR pathway. OPT-302 is currently being developed in nAMD and Diabetic Macular Edema.
The newcomers to this market are gene therapies.
Self-described “leader in AAV therapies”, Regenxbio, is trialling RGX-314 in nAMD and diabetic retinopathy, exploring both subretinal and suprachoroidal delivery. The latter can be delivered in an office setting. RGX-314 utilizes an AAV8 viral vector that carries a gene encoding for an anti-VEGF protein. In essence, it uses the patient’s cells to produce high levels of the therapeutic protein.
Adverum is trialling ADVM-022 in both nAMD and Diabetic Macular Edema, using intravitreal delivery. ADVM-022 utilizes a proprietary AAV2.7m8 capsid, which has been engineered from AAV2.
The goal of both Regenxbio and Adverum is a once-only treatment. However, there are ongoing concerns about waning long-term effect and toxicity of AAV-mediated delivery, as seen recently with a Biomarin AAV8-mediated therapy and an Audentes AAV-5 mediated therapy.
PYC is breaking into the space with a different, “don’t throw the baby out with the bathwater” approach. It is heeding research that suggests that VEGF is not a total villain – while it causes new blood vessel growth which in turn leads to the destruction of retinal tissue, VEGF also supports the maintenance and viability of delicate cells in the retina, specifically the retinal nerve cells. Consequently, VEGF inhibitors may not only remove destructive VEGF, they may also remove VEGF’s critical ‘pro-survival’ signal. Growing evidence suggests that over time, this may lead to retinal nerve cell death and loss of vision.
PYC’s solution, PYC-001, is intended to promote the expression of “favourable” VEGF (VEGF165b) over “unfavourable” VEGF (VEGF165a) during RNA splicing.
If all goes to plan, PYC-001 should offer longer duration between treatments and better long-term outcomes than current VEGF inhibitor therapies and a lower risk profile than AAV-mediated gene therapies.
https://www.regenxbio.com/rgx-314/
https://www.globenewswire.com/news-...wet-AMD-Reports-Recent-Business-Progress.html
https://pubmed.ncbi.nlm.nih.gov/23642856/
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7054566/
https://iovs.arvojournals.org/article.aspx?articleid=2742722
https://iovs.arvojournals.org/article.aspx?articleid=2127492
https://hotcopper.com.au/threads/an...5566385/page-11?post_id=46735838#.X3rFXGhLiUk
(20min delay)