Ann: 2021 AGM Chairman's Address and CEO Presentation, page-54

Ok, I get where you’re coming from now!

While I’ve certainly posted a few times about clinical trial problems with other therapies, especially ocular therapies, these problems have mainly related to toxicity. What those therapies have in common is use of AAV vectors. At the very heart of PYC’s differentiation is its use of proprietary cell penetrating peptides for drug delivery, instead of AAVs.

Your assessment of PYC’s VP-001 drug development program as a risky “moonshot” surprises me. To me, “moonshot” suggests something unprecedented, large scale, with massive cost and very low probability of success – none of which, in my opinion, applies to the VP-001 program. In fact, one of the strongest attractions of the program for me is how it has already been derisked at multiple levels.

Disease area selection– the inherited retinal disease, RP 11. A major advantage in choosing an eye disease is that drug delivery is more targeted, using injections made directly into the eye, thus minimising systemic toxic effects and enhancing therapeutic indices. It’s therefore not surprising that ophthalmology, with a likelihood of approval from Phase 1 of 17.1%, is one of the disease areas in drug development with highest chance of success.

Use of selection biomarkers - Likelihood of approval from Phase 1 for a drug program using selection biomarkers is 25.9%, compared with 8.4% without.

Route of administration - For treatment in eye disease, intravitreal delivery poses less risk than subretinal injection.

Choice of an orphan rather than “blockbuster” indication - Likelihood of approval from Phase 1 for orphan drugs is 25.3%, compared with 9.6% for all types of drugs combined. Orphan diseases also have the advantage of small clinical trials and the potential for a single pivotal study.

PYC’s CPP delivery technology - Preclinical testing has consistently demonstrated PYC’s CPPs to have a superior delivery and toxicity profile compared with other CPPs used in drug development. Delivery is of vital importance in antisense therapy drug development - the greatest challenge to date has been how to deliver a maximum effective dose without off-target accumulation.

Use of patient derived models (human 3-dimensional models of the eye, created from human stem cells) – As a consequence, it has already been demonstrated that VP-001 can restore functionality of the retinal pigment epithelium, the structure that is compromised in RP 11. VP-001 is the first and only treatment to demonstrate restoration of this critical barrier function in a patient-derived model.

PYC’s CSO - Sue Fletcher is a pioneer in the field of RNA therapeutics. She has co-invented multiple drugs that have made it to market and others that are in late stage clinical development.

While there can be no guarantees in drug development, in my opinion it would be difficult to find another drug program at the same stage of development that is more greatly derisked than VP-001.