Here are more questions to CEO Rohan Hockings and I would like...

Here are more questions to CEO Rohan Hockings and I would like to share his comments because a lot of HC members would be interested.

Stages of RP-11 Progression and Possible Improvement in Functional Vision
@Medicine Man
I have prepared a graph just to illustrate the effect of VP-001 for the best case scenario on % Functional Vision Improvement.

• The data points are fictitious and they are for illustration purposes only.
• The “early” group would respond far better as they are younger, and the improvement tappers through to the “middle” and “late” groups.
• However, it is worth noting that patients who had totally “lost” their Functional Vision might be able to regain 5-10% after being treated with VP-001.

[Comments by Rohan]
The 'not treated' graph is more or less correct. With the treated group, however, we are actually hoping for a plateau (horizontal line from the time of treatment initiation) rather than a phase shift to the right as you have depicted here. In reality, it will likely be a hybrid between the two.

It is actually the 'mid' phase patients in your graph that would be easiest to see the treatment effect in (because the rate of decline in the absence of treatment is fastest meaning that, if we were to achieve a plateau, the angle between the untreated and treated lines would be the greatest).

I think you've got the concept here but remember that we are actually looking across multiple endpoints and not a single 'functional vision' endpoint so the picture is more complicated again. We have the Multi Luminance Mobility Test (MLMT) that was used in the Luxturna trial as one of our endpoints and other relevant outcomes include assessment of perimetry of visual field, electrical response of the retina to a light stimulus, the anatomical appearance of the retina, as well as conventional measures of visual function (e.g. visual acuity) that are likely to be less insightful in this specific disease process and some validated questionnaires that reflect the patient's lived experience (known as patient reported outcomes).

Also note that whilst the effect of the drug should be easily observable in the context of your graph, if you zoom in to a single 12-month period and then account for variability in patient performance on different days, the picture becomes a lot more complex.

How is VP-001 being administered ?
@Medicine Man
I have watched a video on Luxturna being administered by subretinal injection https://www.aao.org/clinical-video/subretinal-injection-of-luxturna which looks quite complex.

From memory, VP-001 is delivered by a simple intravitreal injection https://www.youtube.com/watch?v=_ANjxdWnsPc&ab_channel=MarkErickson Is that right?

[Comments by Rohan]
Yes, this is correct - VP-001 has a major route of administration advantage over other gene therapies like Luxturna. It is not only the time/cost/availability of the procedure but also the safety of the procedure and the area of retina treated (less than a quarter of the retina is effectively treated by sub-retinal injection). If PYC had made a drug for RPE65, patients would likely require treatment with both Luxturna and the PYC drug (much like the Spinal Muscular Atrophy patients who have received both Zolgensma and then also receive the RNA therapy called Spinraza).

What is the frequency of re-injection?
@Medicine Man
From memory, it is 3-4 months and you hope to extend it to 6 months for a better patient experience.

[Comments by Rohan]
This is expected to be every 3-4 months as you suggest based on the half life of the drug observed in the non-human primates

Luxturna is a "one shot fix", why would VP-001 need periodic re-injection ?
@Medicine Man
I read Luxturna is a ONE SHOT fix, that’s why the company’s stock code was “ONCE” until it got bought out by Roche. Why would you need to re-inject VP-001 periodically?

[Comments by Rohan]
This is because it acts on the RNA not the DNA like Luxturna (i.e. it is a non-permanent change). There are major advantages of RNA drugs over DNA drugs beyond the route of administration described above - including the evenness of distribution of the drug at the cellular level and retention of endogenous control over protein expression (remember that too much PRPF31 also induces a disease phenotype)

What happens to the PPMO Conjugate once inside the cell ?
@Medicine Man
I understand that the PPMO Conjugate enters the cell through EXON 7 skipping, the RNA drug payload is separated from the PPMO. What happens to the PPMO portion? Would it get absorbed and becomes harmless?

[Comments by Rohan]
The exon 7 skipping is what is occurring in the nucleus of the cell after functional delivery inside the cell (i.e. once the CPP has completed its function). The peptide is made up of amino acids which are likely degraded once inside the cell and then metabolised or re-used by the cell in much the same way that it does with endogenous peptides.

You are more than welcome to post more questions to Rohan and I would endeavour to get them answered