Let me shed more light into VP-001 vs ProQR's Sepofarsen in...

Let me shed more light into VP-001 vs ProQR's Sepofarsen in terms of toxicology.

Sepofarsen was using dosages of 160 micrograms and 320 micrograms in Phase 1b/2 trials, that caused high percentage of participants having adverse reactions such as cataract (8 out of 10), cystoid macular edema, and retinal thinning.

The toxicity was concerning in their high dose (320micrograms), specifically the cystoid macula edema. This appears to be dose related for ProQRS molecule, effecting meaning they hit dose limiting tox in the human. PYC has two reasons to believe this will not be the case for VP-001, even if their doses are similar;

a. PYC's ASO chemistry is different (PYC uses PMOs while ProQR uses MoE chemistries, the image below shows the different kinds). The PMO chemistry is far more inert and hence has a lower chance of driving toxicity.

b. The CPP does mean we should see lower doses in the clinic – and most importantly a larger therapeutic window : the difference between the effective and toxic doses. The Rabbit and NHPs studies has given PYC a far clearer picture on this.

e.g. PYC observed in mice, approx. 20% drug delivery to the RPE cells in the back of the eye at 1.6 micrograms using PMO while zero effect with the other chemistries (including Sepofarsen) at 10 micrograms in the mouse.

The human eyeball is 9.8x bigger than the mouse's, we could approximate the dosage of 16 micrograms for 20% reach, into approx. 80 micrograms needed for 100% delivery to the RPE cells in a very simplistic way. PYC now wants to add a 90 microgram cohort is not without reasons. This is a straight line scaling up and naturally PYC would have a much more accurate calculation.



PYC was expected to have a 6 month interim readout and use 12 months as the target end date for Phase 1 – but this could be extended based on the data they see at 6 months and 12 months. ProQR’s drug QR-421a has a similar disease progression and below is their trail design:



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