Avid Bioservices Inc (CDMO)

[Protector]

BetaBodies jumping Bavituximab!

95% of the posts about PPHM are related to bavituximab, the companies main drug pipeline. The drug has currently not been used in any commercial activity that would stop the clock for patent extension. Hence, upon first approval of bavituximab and expiration of the initial 20 year (17y UK) protection, and in accordance with the US/European patent regulation, PPHM can file for protection extension.

Today we see collaborations with AstraZeneca, of which we know for sure that they contribute in the clinical trials strategy and cost by delivering Durvalumab for free, and Merck of whom knowledgeable posters such as massH estimate that there is a very good chance that they are in some way involved in the up-coming liver trial, possibly not financially - unless we learn otherwise next Q/CC, but almost certainly at least consulted and favourable to the initiative.

PPHM is therefor involved with #2 (and probably commercial #1 given the UK KeyTruda deal) MERCK, and with the #4 AstraZenca in the ranking (or at least consensus) of the Immuno-Therapy battle round one: mono-therapy.

Another consensus is that Immuno-therapy will not survive in the long term as a mono-therapy and that round two will all be about Combination-Therapy. And we all know that you cannot make mayonnaise without at least one amphiphilic substance whether out of an egg yoke or other source. Besides that you can be creative and your mayonnaise can be the basis for a cocktail sauce if you add tomato and whisky, and so on. From there the combination possibilities are endless.

In immuno-therapy the combinations are endless to. The 4 main players alone, not even considering companies like PPHM or all those that are part of the Vice President's Moonshot 2020 initiative, alone own so many antibodies that they can occupy the scientific community for decades in pre-clinical and clinical work to find the best combination.

However, just like with our mayonnaise immuno-therapy needs some GENERIC component to allow these anti-body combinations to be effective at their maximum. What is needed is what is called the conditioning of the tumour environment. It becomes more clear every day that the general MOA of the combo's is to 'light up' the problems in order for the immune system to kick in and take care of it. This can be dome by preventing the problem to be masked and remain invisible from the immune system or by attracting the attention of the immune system to a problem that would otherwise not be anyways visible.

While the PD and CTLA programs have shown that this concept can work it has also shown that it cannot reach its full potential alone because the problem that it fights has itself the unwanted side effects that are the same as during cell apoptosis (which IS actually PD-Programmed cell death). Unfortunately, or for healthy people fortunately, the Immune System is equipped with a number of tools allowing it to not get involved with natural cell death and not see it as a cell or non-body own substance that it must attack and fight. That substance is Phosphotidylserine (PS) a molecule found in the inside of cells that does not get exposed to the blood unless during the cell death cycle. Unfortunately for sure this time, PS is also exposed if the cell is damage due to a viral condition, physical injury, infections/inflammations and yes, cancer-tumours, and therefor erroneously tells the immune system that there is nothing wrong with the cell and that it is just naturally dying. The immune system is deceived and does nothing but clean-up without deploying active counter measures.

PPHM has two molecules in the I-O game of which it holds the IP rights (WW:US/Europe/...) and the pipelines. The most popular one is currently bavituximab that is a non-full human molecule and that needs the presence of substances in the bloodstream to be able to bind to PS. The other one is the next generation that we call BetaBodies, also a trademark name of PPHM, that can bind to PS without the need of blood. This opens possibilities for the blood-brain barrier applications (e.g. Alzheimer) or binding to PS, for instance while it is still not exposed inside the cell where there is no blood, possibly for vaccine applications.

For the PD and CTLA programs to reach their full potential, mainly also in responders, the tumour environment must be conditioned by eliminating the effect of PS. More technically this means that one either REMOVES PS when it gets exposed, an option that is very unlikely because PS only partially ends up in the blood stream in the form of micro vesicles, and otherwise remains on the surface of the endothelial cells that line blood-vessels from where removing them is not an option until we get more advanced in nano-technology (using nanites).

The two other remaining options are to either cap the PS receptors on cells that have one OR to cap the PS molecule itself. In both cases, if one of them is capped, the PS molecule can no longer bind to the PS receptors. Both drugs of PPHM cap the PS molecule and use that approach to prevent PS from binding with the PS receptors. Competing companies such as Roche and Novartis (and several others) attempt to bind the PS receptors. However, their strategies have been designed at a moment that is was not as obvious as today, and certainly the overall MOA not understood as today, that there are MANY PS receptors on different cells that need to be targeted with different substances but MORE IMPORTANTLY that you need to target them ALL TOGETHER. Only THAT counters the fact that the PS molecule itself ALSO tries to bind to ALL available PS receptors on all concerned cells in order to create a complete apoptosis friendly environment (I stole that term 'apoptosis friendly' from a cell biologist I went to talk to at the University :). Furthermore capping the PS receptor is a delicate thing. The molecule that one designs and must bind to a specific PS receptor MAY NOT EMULATE PS!!!! In other words the cell may NOT think that a PS molecule bound to it because if so it will ACT as if one did which makes the drug useless. That is why TWELVE different drug are needed to bind each and every of the 12 different PS receptors (and who knows more then 12).

I did a new round of information gathering, in order to better prepare against the resistance to the theory that binding the PS molecule is better then trying to bind all PS receptors on MDSCs, Macrophages, etc (and it is a long list also including :

IMC: MDSC, Macrophages, T-Cell
TIM: Tim1, Tim3, Tim4
TAM: Axl, Mer, Tyro-3
Others: CD300a, RAGE, BAI-1, Stabilin
source

I have been seeking for factual material that could better support the PS molecule binding then just the reasoning behind it which is mainly based on logic, the MOA and the observed pre-clinical and clinical results that were disclosed. So I wanted to find something behind binding instance and the need of 12 drugs vs 1 and all combination problems involved with that and tremendous dosing challenges, etc, that do not exist with Bavituximab/BetaBodies. Let alone that those current anti-PS Receptor drugs are owned by many different BPs/Parties.

And the answer has been before us all the time in this short movie.
A phenomena that was NEVER EVER observed with any of the drugs that bind PS receptors and that has been observed with Bavituximab as well in pre-clinical (Dr. Brekken UTSW mice dying from old age after second infection with melanoma WITHOUT treatment) as well as several times in clinical trials amongst which the reported work of Dr. Alison Stopeck in one of our Breast cancer trials, is "immune response".

I have never singled in sufficiently on that aspect in order to realise how that differentiation with the competing PS-receptor binding is the MAJOR peace in the claim that ALL PS receptors must be addressed on all cell types at the same time in order to activate the immune response mechanism. And actually capping PS results in creating a condition as if PS wasn't exposed to begin with and hence eliminates all apoptosis side effects that keeps the immune system from detecting and engaging a problem.

Part of that NATURAL immune system reaction is the manufacturing of counter measures for problems the immune system has been exposed to (acquired immune response) in case the problem should occur again. Since such on the fly deviced and specialised counter measure cell recognizes the same problem faster and can activate the immune system, problems do not have the chance to proliferate and can quickly be contained by the immune system.

And it is clear, you do NOT obtain that with PS-receptor binding of one or even a few of the above PS receptors. The MDSC's must be reduced (letting dendritic cells mature) in the tumour environment, TGF-Beta and IL-10 production by MDSC's and M2 Macrophages must be prevented (by not letting the PS molecule bind the PS receptors) and TGF-Alpha and IL-12 must be secreted. The first two prevents Immune system blocking, the second two stimulates immune system activation. The result is an up and kicking immune system with full featured abilities as it would have been would PS not have been abused to make believe that the tumour cells (or viral or inflammation etc cell damage for that matter) are just cells in their apoptosis cycle.

All this is important for patients because it helps prevent relapse of a same problem, read cancer in our case, due to the permanent presence of these problem specific specialised detection cells.

BetaBodies
Our fully humanized beta-Bodies should work better then Bavituximab. They have a lesser dependency (one stage of their binding process, Bavituximab needs a blood substance BBs not) and therefore have a better binding instance (one statistical factor less). They are smaller molecules then Bavituximab and therefore will be more efficient in binding PS on micro vesicle where PS depending on the rip-off is sometimes harder to reach.

So that brings me to the I-O players that we have NOT heard from very much in relation to the Bavituximab clinical trials. Mainly to Roche as the only player that matches the AstraZeneca portfolio and has all programs running. PD-1, PD-L1, CTLA-4 and even a PS-receptor target with Axl.

We all know that this game, actually real war although some on here may not experience it that way, is all about getting approved and becoming SOC so that insurance and social security include the drug in their pay-back programs. And to become SOC you must beat the previous SOC.

Is it still time for Roche to occupy the Bavituximab field now that not only AstraZeneca but also Merck are clearly involved in it and now that the NCCN members are going to run several clinical trials and Memorial Sloan Kettering is working with the drug? What can they achieve? Getting approximately the SAME results as the other PD/CTLA combinations with bavituximab but then much later because the others will again have established SOC before them because they are already on the program. It looks to me that Roche/Genetech has that T-shirt already today in the mono-therapy I-O war where they ended at the best on the 3rd place after BMY/MERCK. It kind of illustrates GILD's CEO statement about BP latency.

Is Roche going to let that happen AGAIN? Probably not, this I-O market will dominate the oncology segment, and possible others, for at least a decade. They cannot effort not to be part of it and miss profits to invest in whatever is next in medical science land. But then why don't we see or hear from them. At the best Roche/Genentech gets mentioned for the use of Bavi-PNG in Digital Imagine and actually not even officially but in some mingling talks at the annual meeting by CEO King and only after being asked a DIRECT and difficult to avoid QUESTION on the matter.

So is it thinkable that Roche talks to PPHM but not about bavituximab. Could they be more interested in trying to break back into the I-O race by skipping bavituximab all together and going for the turbo version, namely BetaBodies? Fresh patents, no competition, no known collaboration so the complete field would be available in one big bite!

One of the serious posters on this board brought the following to my attention (rephrased quote):

Roche's TM for their anti-PD-L1, Atezolizumab is called TCENTRIQ. Look how close this is to PPHM's TALCEPTRX. Kind of reminds us to the PPHM's TM TARVACIN vs ROCHE's TM TARCEVA and finally PPHM backed out of the Tarvacin name.

The TM filing by PPHM for TALCEPTRIX in no way mentions Bavituximab. It has more GENERICALLY been referencing 'antibodies' and that word covers as well Bavituximab as BetaBodies.

It is unthinkable that since the BB patents where filed, about 10 years ago, NO pre-clinical trials would have been done on BetaBodies. It might not have been done at UTSW, or if, it might not have been disclosed. But one thing is for sure, wherever the results are, they exist. What DID change however, since the filing of the BetaBodies patents, is the FDA regulation that today has a BTD program that can be granted for promising drugs and even based on PRE-CLINICAL work without any clinical work. Now would that be the perfect vehicle to move forward with things while keeping everybody in the dark until such FDA grand would be made public, which we know from FDA's Jannette Woodcock will NOT BE DONE by the FDA but is left to the discretion of the sponsor.

Conclusion
The above and what I have posted since the stop of SUNRISE actually extend my list of possible reasons why PPHM, after the SUNRISE stop, invested in taking an international TM in Madrid for the name TALCEPTRX and also filed for a TALCEPTRX logo about 30 days after that. All this while, from where we stand, many say there is not ONE SINGLE program running that gives outlook on a short term commercialisation of a PPHM drug (Bavi or BB) and while the TM may ONLY be used in commercial applications AFTER FDA approval while at the same time there is an NOA issued requiring as SOU response which FORCES IBM to use the name TALCEPTRX in a public and commercial way withing a pre-set time frame.

I wonder if Yuvizo and the other name were ALSO close to OTHER BP's drugs (YUVIZO--> OPDIVO????, TALRIMZA --> anyone? ).

Hence I believe such commercial usage is eminent and as a consequence also some kind of FDA authorisation for the sales of bavituximab. My candidates are (SPECULATION):

- A BLA for Bavituximab in 2nd ln NSCLC based on the complete study including PI and extra data from SUNRISE.

- A BTD, (possibly for breast based on PII data which was really good or maybe even based on the 18 patients that got Yervoy(CTLA-4)+Bavituximab).

- Possibly not a bavituximab thing at all but a sudden BetaBodies move based on yet non disclosed pre-clinical data.

- An application other then Human in the animal or agriculture domain :)

And of course as always if one speculates and names one hundred possibilities it will be number one hundred and one that you didn't think of.