PROTALIX BIOTHERAPEUTICS, INC. (PLX)

[Spideyboy]

Separately, there is a new seekingalpha article out that I would encourage everyone interested to read through:

https://seekingalpha.com/article/4221363-protalix-bridge-ing-balance

The author does a very thorough review.

One of the essential points he makes is that the efficacy of PRX-102 compared to agalsidase alpha (Replagal) provides a clear understanding of PRX-102 superiority on all fronts even when handicapping against Replagal best possible performance.

From a much simpler aspect as far as trying to deduce the potential PRX-102's performance against Fabryzyme in the Balance trial, I have been doing some research in the molecular structure and characteristics of Fabryzyme vs Replagal as essentially these are two isoforms of the same enzyme, just alpha and beta forms. Thus my hypothesis being that if these two are the same and PRX-102 performs significantly against one then it ought to do the same against the other.

Fortunately there have been recent papers that make comparisons between these two available ERTs. Key documents links are at the end of the post as they are rather long URLs.

Here are the essential takeaways from my research.

Fabryzyme and Replagal are very very similar indeed (this is of course to be expected)

Production is different in that Fabryzyme protein is produced in Chinese Hamster Ovary (CHO) cells, where as Replagal is made in and undisclosed manner involving human cell line expression system.

Despite being designed on the same piece of DNA, the protein expression production systems being different will create slightly different proteins, mainly due to sugars and other elements that 'pop' out from the enzyme which provide it with differential behaviour in biodistribution, immunogenicity and target cellular uptake. More uptake is better as this mean the enzyme is getting to where it needs to act.

Between Fabryzyme and Replagal, it appears:
"There was no difference in the slope of eGFR between agalsidase alfa and beta in patients"

Fabryzyme is better at cellular uptake, but also causes more anti-body formation which breaks down Fabryzyme at a faster rate.

Therefore while Fabryzyme appears to have better activity when it gets into the cell, it may be broken down more easily and therefore less of it getting into the cell.

Whereas Replagal will have less of an anti-body attack against it, but may be less efficacious when it gets into the cell, but not a significant clinical difference.

In general this may explain the fact that despite being the same enzyme, Fabryzyme dosage is 5-fold greater than that of Replagal. e.g. Fabryzyme 1mg/ml/kg, vs 0.2mg/ml/kg.

One may therefore consider that Replagal to be a less effecive product than Fabryzyme and thus wonder if PRX-102 being the same alpha isoform as Replagal, that perhaps this might mean that the intrinsic structure of PRX-102 might also be prone to being slightly less efficacious than Fabryzyme.

However this, I believe, would be a poor understanding to come to based on the following 2 key points.

1. PRX-102 is not produced in CHO cells nor human cell lines, but is made in plant cells. Therefore one cannot directly compare replagal potential construction design issues to PRX-102. And given that this is a clear impact on functionality, one might expect Protalix to have taken this into account for their protein production system.

2.Even if, PRX-102 might potentially have similar post-translational modification issues as Replagal, the actual clinical benefit between Replagal and Fabryzyme was indistinguishable. Albeit with a slightly but not significant slower uptake or replagal into the target cells. Now consider that even if PRX-102 might be slightly slower for uptake, the more important fact to take into account is that PRX-102 has 40 times the current ERTs' half life meaning that even if it might be slower it doesn't matter as there is so much more available in the body that it will be by definition have a much larger uptake into target cells, simply because a significant amount of Fabryzyme and Replagal will be broken down before having the chance to get to the target cell type, and even once there will still be broken down faster.

3. As noting at the beginning these research papers see: "There was no difference in the slope of eGFR between agalsidase alfa and beta in patients". Thus if PRX-102 appears significantly superior to Replagal then it would stand to be significantly superior to Fabryzyme in the Pivotal Balance trial.

Thus the far greater bioavailabiity of PRX-102 in the target cells should provide significant benefit over either Replagal or Fabryzyme.

Therefore from the BRIGHT data it would seem there is very much great promise and I would say highly likely greater superiority of PRX-102 over Fabryzyme as well as has been demonstrated thus far against Replagal.

Also PRX-102 is not being given at the lower Replagal dose, but is being given as the higher Fabryzyme does of 1mg/ml/kg which provides that much more bioavailability of PRX-102.

[P.s. I might note that curiously the nonsense and likely paid basher C.C. Abbott has managed to not make a peep yet against the Bright Interim data set and hasn't interjected in some ridiculous manner on the latest seekingalpha article. I do hope she's gotten the point by now that she has been woefully wrong in all of her PRX-102 analyses. Again her prospective nonsense on the Bright interim data without having actually seen the full data presentation was as low as you can go so far from her]


https://jmg.bmj.com/content/55/5/351

https://watermark.silverchair.com/cwg034.pdf?token=AQECAHi208BE49Ooan9kkhW_Ercy7Dm3ZL_9Cf3qfKAc485ysgAAAjAwggIsBgkqhkiG9w0BBwagggIdMIICGQIBADCCAhIGCSqGSIb3DQEHATAeBglghkgBZQMEAS4wEQQMhm6i-b2wOf4y_KzqAgEQgIIB42TF9K914CHzz3_ZEv2rMWs3yLln8_myMczapaN1MZarV6-NLQHdGExeMbsThjxsDIX0bSc3diF0gu43YsvR829duqA38Y31g1oS93OQjrNcZyrjeaBdtzwmHl-Igymk3aUyWE7vNT9voqWorGwtyxPRGHoGLEXFWujUcQVmcFLp7nXVL352YG9srWydPXNuDPXky2I1EjMP8mUJLAR-WJKm4OhxrjDTrpuO1SDuZdUKb76Z8jDZXvMh-cQj4406ndJCuv3Ep914cOrDTOw8Wz560rt8NBAKwM6rBpwdcw2efEOSj-d5RZW7C1Xj42jjozowYmi-ysCA5MzMEqOlxJ8wkv_LWcLzlm9DqsI5pHLAvSLIye-jKQktUtLn6UB10L8-F9adhOzEs3KTctpw9vOXRp_RV3YxNChdMStaEG1kF8K3G24cWbpjy7A6xKKzp9guD5m0rbulyn-Q3qZLrjyZvlYSDoZwSQVe1_T2WDYdVr33Djpk3Ghsn_wCT6OPPbiXtzKEWmvUa8z8iAEhMc_yRi-hyk-QstamnYBFzyVvipli8GqB50QzCaGWUjZ7Vue8_erAzaE2TcRKQXR5TwwcIFvH8gf9w9lIt1r6pMlYTSfdmcgmV0AWy8F-eIqnfP7MPA