For a refresh (my brain often needs one!), I’ve compiled a...

For a refresh (my brain often needs one!), I’ve compiled a summary of PYC’s lead drug, VP-001 from information provided in company announcements and presentations over the past 6 months (1/4, 22/6, 22/7, 7/10).

The Indication

• There are currently no approved drug products for Retinitis Pigmentosa Type 11 nor any drugs in clinical development to address this severe unmet patient need.
• The size of the target market is estimated to be 1-2bn USD p.a.
• FDA regulatory pathways for rare drugs include: Orphan drug designation, Fast track designation, Accelerated approval, Priority review, Priority review voucher

The Opportunity of Rare Genetic Diseases



Safety

Dose limiting toxicity is currently the rate limiting step for precision medicine. Competitor ASO technology currently in Phase 2/3 clinical development showed inflammation (a sign of toxicity) at 100μg in the rabbit eye and dose limiting toxicity at 320μg in human patients. PYC’s mouse model results safely used a maximum 6.4μg dose, which translates to ~1,600μg in the rabbit (16x the dose at which the ‘naked’ competitor ASO demonstrated toxicity). The ability to safely dose at these relatively high levels illustrates one of the competitive advantages of PYC’s CPP-PMO therapeutics.


Efficacy

Increased level of phagocytosis in diseased RPE cells

When administered to diseased Retinal Pigment Epithelium (RPE) cells, VP-001 successfully mediated restoration of the scavenger function/self-repair process that is lost in Retinitis Pigmentosa type 11 (RP11). This self-repair process is known as ‘phagocytosis’ and it reflects the ability of one layer of cells in the back of the eye (the RPE) to clear away debris from the cellular layer above (the photoreceptors).



Increased cilia length

Another feature of retinitis pigmentosa is shortened cilia length in the RPE. Shortened cilia are indicative of poor cellular health and are likely to be related to the reduced functionality of cells in patients with this disease. VP-001 successfully increased the cilia length in diseased RPE cells to levels seen in individuals without the disease – an indication that the health of the cells after treatment is substantially improved.



Increased exon skipping

VP-001 demonstrated positive outcomes in 3D models of patient retinas known as ‘organoids’ or ‘retina in a dish’. The ‘retina in a dish’ models confirmed the ability of the drug molecule to enter the nucleus of cells and induce exon skipping of the target gene message. This result explains the ‘mechanism of action’ of VP-001 and more broadly validates the effectiveness of PYC’s delivery technology and the potential of its retinal pipeline of ASO therapies.



Increased PRPF31 protein

RP11 is caused by a mutation in the PRPF31 gene which leads to abnormally low levels of PRPF31 protein in the Retinal Pigment Epithelium (RPE) and photoreceptors in the eye. Correcting the levels of PRPF31 protein inside the target cells should, therefore, lead to correction of the disease process as a whole.

VP-001 demonstrated increased PRPF31 protein in models derived from patients with different mutations in the PRPF31 gene. The median level of target protein upregulation across these patients was ~1.6-fold at the anticipated human dose – well above the expected threshold of 1.2-1.3-fold required for correcting the disease.

These results provide the strongest indication to date that the drug will be effective in all patients with RP11 when the program enters clinical development