PYC’s Lead Investigational Drug, VP-001, Demonstrates Another Key Functional Improvement in Patient-Derived Models

PYC Therapeutics announced that the company’s lead investigational drug, VP-001, for the treatment of RP11 has restored function of the retinal pigment epithelium (RPE), the target cells for the therapy, in patient-derived models of the disease.

“This result builds further conviction in VP-001 as we head towards clinical testing. Break-down of the Blood-Retina Barrier is a major driver of vision loss in patients with RP11. This result has given us the best non-clinical demonstration that VP-001 has the potential to correct this problem in patients,” PYC’s US Chief Executive Officer Sahm Nasseri said in a company news release.

The RPE cells create a barrier around the outside of the eye when the RPE cells join together through ‘tight-junctions’ that form between individual RPE cells. This ‘layer’ of RPE cells form the outer Blood-Retina Barrier (BRB) that prevents fluid from leaking into and damaging the retina.

“The individual RPE cells act like bricks in a dam; they all work together in stopping large amounts of fluid flowing directly into the retina. At the same time, they allow for the controlled flow of nutrients to keep the retina functioning and enable normal vision,” commented PYC’s Chief Scientific Officer Prof. Sue Fletcher.

In patients with RP11, two elements of the RPE function are lost:

1. The functionality of individual RPE cells (PYC’s VP-001 has previously shown effectiveness in correcting this loss of function, see ASX announcements of 1 April and 16 December 2020); and
2. The role of the RPE monolayer in the BRB. The barrier function of this monolayer is created through tight-junctions that form between all the RPE cells. If only a few of these tight-junctions fail, then the integrity of the whole BRB is comprised – just like taking a few bricks out of a dam wall.

VP-001 has now demonstrated an ability to restore the integrity of the blood-retina barrier that is lost in patients with the disease, in models derived from patients with RP11. This development indicates that VP-001 can more comprehensively address the mechanisms of the disease that lead to visual loss in patients with RP11 than alternative therapies tested to-date. These data provide the first evidence of restoration of the barrier function of the RPE monolayer and add to the previously released efficacy data for VP-001 demonstrating an ability to correct the functional deficits seen in individual RPE cells in patients with RP11 (see ASX announcements of April 1 and December 16, 2020).

This achievement differentiates PYC’s RNA approach from Adeno-Associated Virus (AAV) delivered DNA therapies directed towards the treatment of RP11 that have not been able to demonstrate an improvement in these functional endpoints in non-clinical testing[1].

In addition to the results supporting improved barrier function of the RPE monolayer, correction of the morphology (the ‘structure’ of the cell) is shown after treatment with VP-001. This quantifies the visual evidence of the improvement PYC demonstrated after treatment with VP-001 (see ASX announcement of December 16, 2020). 

“Patients with RP11 are desperately waiting for a treatment option. These data shared today represent exciting progress for VP-001 as PYC strives to elucidate the potential of this breakthrough RNA agent as we advance towards the clinic. Beyond these results, we look forward to sharing continued progress for VP-001 through our important large animal studies in the middle of 2021, with the goal of submitting an investigational new drug (IND) application to the FDA during the first half of 2022,” concluded Sahm Nasseri.

[1] Brydon EM, Bronstein R, Buskin A, Lako M, Pierce EA, Fernandez-Godino R. AAV-Mediated Gene Augmentation Therapy Restores Critical Functions in Mutant PRPF31+/- iPSC-Derived RPE Cells. Mol Ther Methods Clin Dev. 2019;15:392-402.