PROTALIX BIOTHERAPEUTICS, INC. (PLX)

[Spideyboy]

Thanks for finding this, in summary, interesting but not exactly blown away at the moment and presently not looking like a strong competitor.

Regarding timelines, I compare against Bluebird Bio which is much further along development in the gene-therapy space and also looking at their beta-thalassemia development as this, like fabry is also a rare disease.

For Bluebird, it took them 5 years to complete a phase I/II study on 18 patients.
https://clinicaltrials.gov/ct2/show/NCT01745120?term=LentiGlobin&rank=5

They have 2 phase III trials looking at 2 different types of beta-thalassemia patients which are both expected to take another 4-5 years, each trial recruiting 23 & 15 patients (for a total of 38 patients).
https://clinicaltrials.gov/ct2/show/NCT02906202?term=LentiGlobin&rank=4
https://clinicaltrials.gov/ct2/show/NCT03207009?term=LentiGlobin&rank=3

So we are looking at at least a decade with regards the clinical research time-frame for Bluebird Bio, probably about 12 years with regards the whole timing.

Now comparing that to Avrobio:

They have one clinical trial registered and which started on Feb 2018, for 12 participants and the company says it expects to end in 2020, giving it an expected 3.5 years to completion.

On this first point it would appear that Avro is quite far behind on that timeline, as based on the October 2018 presentation you provided, it would appear they have recruited 4 patients thus far. Note that the clinical trial is set to follow them for 48 weeks for the Primary outcome measure. If in 1 year they have a confirmed recruitment of 4 and perhaps if we are lenient we can say 5, then at that rate they will need at least another year and a half to complete enrollment, and then get the read out, so we are looking at about 2021-2022 for this study's completion at this time. They could of course try to bring on more sites to speed things up, but you need a site that can do gene-therapy trials which I assume is harder to license than just a PRX-102 infusion.

Then of course they will need a Phase III trial with what can be expected at least about 30-40 patients. Needless to say based on their current recruitment times, this may take many years and probably with a longer time-frame of the trial itself than the Phase I/II which is essentially powered for safety/not efficacy.

Regarding the actual longer time-frame for a potential Phase III trial itself, I believe this would be requested by the FDA based on the type of longevity of efficacy we are seeing from the presentation's data (Slide 11).

Here we see that after dosing, there is a quick increase in the patients production of galactosidase alpha, peaking for Patient 1 at 6 months, and peaking for Patient 2 at 3 months. After peaking we appear to see a constant decline in galactosidase alpha production. Looking at the higher performing Patient 1, at 18 months post-dosing he is already 2 points away from reverting back to the classic fabry situation he started with.

For Patient 2 we see a much faster decline after peaking, and with apparent return to classic fabry levels as early as withing 9 months post dosing, and definitely looking like 12 months is the maximum length of time the treatment will last for him.

From what we can make out for Patient 3 on slide 12, the Vector Copy Number (VCN) 1 month after treatment is equal to that of Patient 1 at 18 months, which may indicate that the product will have little treatment benefit within a dramatically shorter time-frame.
(Note "Vector Copy Number" shows the relative amount of copies of the new gene of interest that is in the patient's cells. The higher this is the more gene copies we have, the greater the potential gene-expression. If this is low then we have lower expected gene-expression and at 0 we should have no gene-expression)

As it stands with the current Phase I/II trial we cannot see for Patient 1 what their efficacy situation will be after 18 months, I would expect the FDA will want to see at least up until month 24 in a future Phase III trial.

Thus based on their provided data it would not look like a 'cure' to me at all. But perhaps a longer time-frame between dosing.

Now the question is, if based on Patient 1 data that this product will be valid for 24 months post-dosing, how expensive will it be to re-dose ever 2 years, compared to PRX-102 dosing every 2 weeks or every month based on the current PRX-102 clinical studies. (This of course doesn't take into account safety considerations which I go into later)

Gene-therapy is still largely just getting to the finishing line with the first indications and as such will be extraordinarily expensive. Now if you can tout it as a full-on cure and once in a lifetime treatment then one can justify the costs. But if at present it looks to be at best a re-dose every 2 years, or if based on Patient 2 every year, or potentially based on Patient 3 even less time, then I believe it will be hard to justify Avro's probable product price point over PRX-102's, when we consider the Fabry situation. (beta-thalassemia has virtual no treatment except for constant transfusions).

Additionally, one has to take into account physician likely acceptance of the product. PRX-102 is a long-lasting form of a product that is already on the market which the physicians are very familiar with, thus acceptance upon potential approval should be quite favourable. Then assuming in about 2028 this gene therapy product gets approved then switching from familiar ERT to Gene-therapy which does not appear to have true curative potential will be a more difficult switch-over I believe for the physicians to accept, unless of course the final data shows significantly longer and/or true curative potential.

Also regarding efficacy parameter relevant to physician and regulatory acceptance, I would expect both these stakeholders to want to see the eGRF slope change data. However in this Phase I/II data, Avrobio's assessment does not include this, only using "reduction of substrate in kidney biopsy" as the primary efficacy end-point. This being the same as the GB3 inclusion reduction used by Fabryzyme and Galafold to gain the Accelerated Approval, but which required/require full eGFR data anyway in a follow-up trial.

If I were a physician I would rather go with a product with proven eGFR slope improvement. The fact that Galafold doesn't have this yet, is perhaps one reason which Galafold's sales haven't seen as strong an uptake as one might expect.

Regarding other data (slide 16), looking at the 1st patient dosed under the Phase II designation, we see then galactosidase alpha peak on day 56 (2 months after dosing) at 3nmol/hr/ml, (1.2nmol/hr/ml is normal levels), and then the galactosidase alpha levels drop again as seen in the previous patients' data sets. If we assume this patient's slope of decline to continue we might expect to return to Fabry levels at latest about day 280 so within 9 months of dosing, but probably earlier.

For this patient the VCN values are also a bit odd, going from 0.7 to 0.2 within the first month, then month 2 is also 0.2, and then up to 0.5. This would be great if after the reduction in VCN, the body would then see greater levels, but this data appears inconsistent with the previous 3 patients which show a continued decrease in VCN over time.

Regarding slide 20 and 21 looking at Neutrophil and Platelet counts, I'm not sure why this data is included as these are not things that are affected by Fabry. My only thinking at this moment is that given we can see both of these drop significantly after dosing, that decrease from normal Neutrophil/Platelet levels to 0, is being caused by the chemotherapy agent Melphalan treatment (as noted on slide 20), due to the fact that the gene-therapy drug is being injected via Viral particles and therefore you would need to disable the patient's immune system (hematopoeitic system) for enough time so that the Viral particles have the time in the body necessary to infect and transfect the new DNA into the patient. Then after enough time has elapsed and we hope for enough transfection to have occurred we allow the patient's heamotopeitic system to go back to normal.

However as far as I can tell that sounds terrible. You can see that from day 7 to 12 both patients have 0 Neutrophil count and need up to day 17 for Patient 2 to get back to normal, and by day 30 Patient 1 is still near 1.5x10^9/L (note normal neutrophil levels require a minimum of 2x10^9/L). This meaning that the patients will be easily susceptible to any simple infection/cough/cold as they have no protection.

Similarly regarding Platelets we see significant drops and reaching 0, which puts these patients at very high-risk of bleeding both outwardly and internally. Minimum normal platelet levels are 150x10^9/L. Patient 1 is below that level from about day 6 to about day 18, and Patient 1 is below that level from about day 1 to day 25. Not exactly ideal, and definitely not looking great for physicians who might be looking to get their patients on this product. And when hopefully the alternative of PRX-102 is already on the market.

Under the current circumstances I can't say I'm exactly impressed with this drug's curative potential and potential risks involved. Additionally, while I know slide 19 says the 2 serious adverse events were not treatment related, dehydration and vomiting, probably from the hematopoetic system suppression drug Melphalan don't sound great.

All this compared to PRX-102's apparent reversal of the eGFR slope using a longer acting form of a familiar product and with an excellent safety profile and with 2 week or 4 week dosing regimen, seems a far better option for physicians and patients to me.

I agree with what they are trying to accomplish and for patients I do hope it does work, but based on this data and the timelines, I wouldn't consider this to look like strong competition at this time nor in the next 8-10 years. However if new data looks stellar that could of course make it a viable competitor. It will be worth checking on these guys every now and again.

Thanks again for the find!