Protalix BioTherapeutics Inc (PLX)

[Spideyboy]

Hi Kronberg, an interesting topic looking to the future, but I do not consider these as issues for PLX or PRX-102 or do not consider these in a sense 'real' treatments at all for Fabry.

My reasoning is primarily based on the fact that both these SRTs are looking for clinical endpoint relating to the reduction of GB3 or GL1 to GB3 reduction in the blood vessels, e.g. Plasma GB3, which then impact on skin GB3 levels which then impact on the Pain sensation produced by Fabry disease when GB3 builds up in the skin cells.

While of course helping Fabry patients resolve the levels of pain they experience in the skin is of course very important it has 3 very important caveats.

1. It doesn't help with the degradation of the kidneys, which is the most common cause of death in Fabry patients and most commonly the fastest progressing issue.

2. It doesn't help with the heart function degradation, which is also a cause of death

3. Using pain as an endpoint is clearly a very subjective method of reporting. And we know that physicians and the FDA are far more fond of objective endpoints and ones that correlate to a significant clinical benefit, of which keeping a patient alive for longer is usually considered of paramount importance.

Before going into each product specifically we note both of Lucerastat & Venglustat are Substrate Reduction Therapies (SRTs) with the following same action, but I copy paste from an article on Venglustat which describes it nicely:
"oral inhibitor of an enzyme called glucosylceramide synthase (GCS). Enzymes modify specific molecules called substrates. GCS turns its substrate, ceramide, into glucosylceramide (GL-1) during lipid metabolism, a series of biochemical reactions that degrade and generate lipids. GL-1 acts as a substrate to other enzymes and is turned into globosides, a subclass of lipids where Gb3 belongs.

When venglustat inhibits GCS, it prevents the synthesis of GL-1, thereby reducing the substrate of the following reactions that lead to the formation of Gb3 and its accumulation in the absence of a-galactosidase A. That’s why venglustat is called a substrate reduction therapy."

https://fabrydiseasenews.com/venglustat-ibiglustat/

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Now specifically speaking on each SRT's situation:

Lucerastat:

Phase III clinical trial endpoint is Pain which as described above is a subjective measure and not that great specifically regarding keeping patients alive.

Secondly the Phase III trial is investigating Lucerastat as a MONOtherapy vs placebo if you believe it. Which means that in the trial they are not even going to be giving ERT to the patients.

The prior Phase I which showed interesting results was at least in combination with ERT to provide some sort of support to the patients.

Thus the Phase III design is in a sense dooming the patients and their physicians to accepting providing no clinically beneficial product to the patients when there is some available and that the new monotherapy is not even being investigated to improve the basic important clinical outcomes of Fabry disease.

Not a good trial design.

Secondly, initially they planned to enroll 100 patients acorss 29 sites in 9 countries. We can see that hasn't worked well for them at all, as currently on the clinicaltrials website, they are now planning for 108 patients across 58 sites across 15 countries. But while 23 of the planned sites are still not yet recruiting.

Also Perhaps the increase of 8 is also due to drop-out of the initial patients?
https://www.idorsia.com/media/news-details?newsId=1680642
https://clinicaltrials.gov/ct2/show/NCT03425539

This Phase III was started in May 2018.

With regards potential time-frame to completion let us remember that it took Protalix 3 years to recruit the 100 patients needed for the BALANCE and BRIDGE studies. And that was with good pre-clinical data on Heart, Kidney function and better than current ERT data from Phase I/II on eGFR slope data in humans.
BALANCE the largest of the PLX studies with 78 patients recruited from 51 sites across 21 countries.

So we can see that it's not going to be easy to get patients into this trial.

And we know this isn't working out for them as on that presentation that Dr Warnock made last December, he stated without mentioning the name that there was a study in Fabry looking to use Pain as its primary endpoint, but for which as per explained above they are having issues with enrollment, surprise surprise.

Thus given the May 2018 start, the minimum 3 years to recruit if all centres are online, but that presently half of them are not, would put the timing to enrollment at a logical 6 years, but then add the lower reason for patients and physicians to enter the trial would probably put enrollment at about 9 years, even as new sites come online?? Then the endpoint in pain is at 6 months, so we are looking at about 10 years to data from this study??

If PRX-102 is approved it will be even more difficult to find the patients physicians wanting to enter this monotherapy trial. Even if it does complete the data are largely meaningless without heart or kidney function assessment in addition to nothing to compare against.

Venglustat

Again Venglustat is the same mechanism of action.

As far as I can see on the clinicaltrials website looking for Venglustat/ibiglustat or GZ/SAR402671, For Fabry, there are 2 Phase II trials listed for Venglustat and no Phase III trials.

One of the Phase II trials Started on July 2015 ended in Nov 2018, with a total of 8 patients and the other Phase II trial started in Nov 2014 ended Sept 2016 of a total of 11 patients
https://clinicaltrials.gov/ct2/show/study/NCT02489344?term=GZ%2FSAR402671&draw=2&rank=1
https://clinicaltrials.gov/ct2/show/results/NCT02228460?term=GZ%2FSAR402671&draw=2&rank=2

The first of these 2 mentioned, looked at Adverse Events and other abnormalities, the second looking at GL-3 in Skin capillaries & Plasma GL-3.

Again not great things to investigate as per all of the above.

One also notes that both these studies for Venglustat ended by 2018 and there was no follow-up to Phase III, need I explain why I'm not surprised.


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Thus in conclusion:

- It seems Venglustat was dumped by Sanofi Genzyme and will never come to market for Fabry,

- Lucerastat is not having a good time with recruitment at all, and could take them maybe a decade to complete the current Phase III and that even if it does complete that Phase III the results will largely be useless. The only key advantage I can really see for Lucerastat is its ability to pass through the blood brain barrier which might help with the CNS issues of Fabry which a full sized enzyme cannot get through and treat, but that sort of CNS endpoint hasn't been looked at in any of the SRT trials for Fabry. If they do conclude this Phase III they may indeed need another Phase III against an active comparator, which if approved I believe would logically be PRX-102.

These do not appear of concern in comparison to PRX-102 at all, with its efficacy on Plasma GB3, Lyso-GB3, support of Kidney Peritubular Capillaries, heart and kidney uptake of PRX-102 and long-term data so far all evidencing significant superiority over commercial ERT on the all important eGFR slope and lower to no immunogenicity a key issue of current ERT. Needless to say with this amount of efficacy and the 40 times greater half-life, pain scores will decrease too, as which was in fact observed in the Phase I/II PRX-102 trial.