The last mention by the company of CNS was during the AGM in November.
Travelbug wrote after the AGM
My main take away was that the 3-5 drugs are all coming along quite fast behind the first and the platform validation is of particular interest to the USA, esp in the CNS. Also systemic delivery seems like its a thing now as well, which is a game changer for later imo.Indeed, in the Chairman’s Address, Alan Tribe said
Based upon RNA technology a pipeline of drugs has been developed all targeted in the eye….
However, it is important to remember that the drug delivery platform has the potential for a much wider range of applications. Some of these are being studied in-house such as the Central Nervous System and the kidney. There is also considerable opportunity for PYC to work with other organisations that have developed drugs which could benefit from this delivery technology.
At the AGM, in his “Outlook for 2022”, CEO Rohan Hockings looked forward to
New target tissues (CNS etc.) and new dimensions (specificity) added to the Company’s proprietary RNA modality.The last major update on the CNS preclinical program was 9 months ago, when results in a mouse model were announced. PYC’s PPMO was said to have demonstrated significant delivery advantage over other RNA chemistries in the brain (ASOs and naked PMOs).
Because it’s a while ago, I’ve reproduced some of the announcement below
A major barrier to development of precision medicines for neurodegenerative disease has been the poor delivery of these medicines to the brain. Insufficient depth of penetration and therefore inadequate delivery to target cells, has prevented drugs from having meaningful impact on these diseases, without causing significant toxicity. This has been especially true for naked PMOs (i.e., PMOs without a delivery molecule), which have particularly poor uptake in adult mouse models, hampering their otherwise ideal safety, durability and target engagement profile—benefits that set PMOs apart from other RNA therapeutics such as Antisense Oligonucleotides (ASOs).As PYC has been previously able to show in ocular diseases, today’s highly encouraging results demonstrate PYC’s PPMO technology has significant potential to solve this delivery challenge in neurodegenerative diseases. Superior delivery and an excellent short- and long-term safety profile in preclinical models could translate to a higher probability of clinical success and ultimately the creation of truly differentiated and meaningful medicines for patients with significant unmet need. Here, PYC has demonstrated PMO delivery and antisense effect at dosages significantly lower than those reported for delivery of both ASO and other RNA therapeutics, and using research-grade material that may under-represent the true efficacy of PYC’s PPMOs ...
For this study, PYC researchers led by Prof. Sue Fletcher, Chief Scientific Officer of PYC, administered either a PYC PPMO drug, a naked PMO, or a PS ASO drug of the same sequence, via intracerebroventricular injection into mice. On day 5 following treatment, the PPMO demonstrated a dose dependant response across the target areas of the brain including both the motor cortex (focus in ALS) and the midbrain. Further, there was no evidence of efficacy for the ASO or naked PMO at any dose tested in this model. PYC also tested the PMO with additional Cell Penetrating Peptides (CPPs) from the PYC peptide library (each n=1 result) at 1 nmol dosage and observed improved exon-skipping over the current PPMO. While this result is not yet significant due to small sample size, it indicates that PYC’s CPP library contains multiple CPPs that are potentially even more effective for Central Nervous System (CNS) specific delivery…..
Our team is now running experiments to determine the cellular level uptake of the PPMO in the brain – ensuring we deliver to the right cells is the next major de-risking milestone for the CNS PPMO platform.”
While PYC is leading its development pipeline with rare eye disease drugs, it’s been made very clear that it is application of the drug platform technology in CNS that has generated particular interest, especially in the US. The company has previously suggested that the first CNS indication will be a more mainstream neurodegenerative disease. While this may generate more interest than a fairly rare eye disease, clinical development will also be much more expensive, in which case a partner will probably be needed from an early stage.
Hence my interest in the value of the Biogen/Ionis licensing deal for a preclinical CNS antisense asset in one indication, keeping in mind that SMA is still an orphan disease and three approved therapies already exist. US$60m upfront + development, regulatory and commercial milestones + royalties with all future costs to be paid by the licensor sounds pretty attractive to me.
It will all come down to the data. The early data in a mouse brain model, in which a PYC PPMO was pitted against both a naked PMO and an ASO, certainly sounds like a good start
….the PPMO demonstrated a dose dependant response across the target areas of the brain including both the motor cortex (focus in ALS) and the midbrain. Further, there was no evidence of efficacy for the ASO or naked PMO at any dose tested in this model.
(20min delay)