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TOPIC: Biding The Time...again.

Biding The Time...again. 07 May 2017 11:48 #9286

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Someone wrote me sometime ago- those 4 months until the read-out of the Scleroderma data, will fly by and will be there before you know it.
Roughly one month passed by sofar and on the contrary- time is not flying by, the days are like chewinggum, they seem to get longer all the time.
Actually, that should not come as a surprise. Guys like Rongside and myself have been liaised to this "club" since 2000- i.e. over 15 years, of which -for me- about 11 years have been rather intensively dedicated to following the science also. All that, might come to a crashing halt in Q3 and I- and surely many others- will pack it in than, when Scleroderma data are not as expected. If they are- (which I strongly believe) - a whole new era for the Company and the science will start.
Anyway- one can take it all in a positive way, since I think CCT is rather holistic and it brought me as a former pill-popper, on the track of Naturopathy, which replaced my quest for SC knowledge the past 2-3 years. Quite a change for that pill-popper yes, who´s wonderful elderly female practioner in 2005 measured serum levels for me on her own budget to help me, but idiotic me, refused to take her recommended B vitamins, since I believed my pills, statins, beta-blockers and a lot more of that junk, should do the job. The results were MI, cancer and insulin resistance i.e. type 2. Life is strange- now I am probably healthier- at 68 soon- than I was at 45. Strange how life plays out.
Anyway- I wrote this as Intro to this thread- I will simply add small- not really important things to this Biding the Time topic- just to keep busy a bit and trying to escape the chewing-gum.
I have a bookmarks folder filled with links with all kind of different stuff- they will appear here- one every day, just so we pass the time until D-Day.

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Board moderator and Site-owner. I still regret the day I started analysing the prospects of MacroPore (now Cytori) back in 2004- a left-over from the tech-bubble at that time from the century change in my portfolio- and became addicted to Cytori´s fat cell technology. :cry:

Biding The Time...again. 07 May 2017 17:28 #9287

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Azaya and Trinity were all founded by Chandra Singh and the central liposomal invention is Protein Stablized Technology PSL). Chandra Singh, probably an Indian pharmaceutical chemist, left Azaya many years ago. Though there were some legal dispute between Trinity and Azaya regarding this central technology. By now, it is clear Azaya holds the patent and CYTX holds the right in this AZA-CYTX marriage.

I am not a basic scientist. My background is all in clinical pharmacology of cytotoxic drugs.

Based on what I can gather, John Kerr who owns the AZA assets is willing to give Hedrick the PSL, which is essential in Hedrick's new preclinical works in regenerative medicine - druggable and off the shelf, free of cells. Kerr's family is very supportive of Hedrick's new works, with current r/d focus in scleroderma and then other clinical applications. In exchange, CYTX would continue to bring lipo doxo and lipo taxorine to the market. CYTX cannot sell the ownership or license out the products, but CYTX can partner with others to further developing the products and marketing.

The lipo doxo for EU approval and marketing with a distributor) is easy work for the rest of the r/d - validation of the San Antonio AZA manufacturing plant with test batches. Finding an EU distributor is no sweat.

For US approvals, CYTX should have not problems with the lipo doxo - the major work is a bioequivalent study in CANCER PATIENTS! All cytotoxic drugs are carcinogens - they cannot be given a normal human volunteers, thus the clinical trials can be slow. There are not many US oncology centers and hospitals available to do this kind of clinicals. CYTX can go to U of Texas San Antonio and its sister oncology hospital at University of Arizona (both have been strongly influenced by Dave Alberts and Dan Von Hoff). Maybe it can be done at Roswell Park or MD Anderson. But, not easy to do this kind of bioequivalence in cancer patients.

The lipo taxorine, based on my understanding, is considered a new cancer entity. Thus the clinical trials can be expensive ($ 100 million). The clinical trial is not just a simple bioequivalency test. The whole clinicals to NDA (solid tumors, no haematologic disorders) takes about 5 years. It has to do just with money. Phase I: very simple, dose escalation to MTD and then back off - one year in 2 centers (about 30 patients in each center). All in cancer patients -experimental cancer therapy. No sweat - open label. Phase 2- open label in selective tumor types (1-2 years). Phase 3 - randomized trials in just one targeted solid tumor, lipo taxorine is added on or replacing another drug in a cocktail of cancer drugs (2 plus years).

Unfortunately Dr. Marino is not a cancer clnical pharmacology and he has not background to do this kind of oncology clinical testing.

CYTX does not have the money to do the lipo taxorine clinical development - CYTX needs a partner. It is not hard to find.

Liposomal doxo marketing successes will spill over to liposomal taxorine development interests. I think liposomal doxo can easily bring $ 100 million yearly revenue.

Actually, I think the excitement re AZA is really what Hedrick is doing in the iv, druggable, off the shelf, liposomal regenerative medicine. He is very, very secretive.

I know as a fact John Kerr is very supportive of Hedrick's works for the next generation of sclerodemra treatment.
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Biding The Time...again. 08 May 2017 07:09 #9288

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Franshei,

Very interesting background. You are helping me understand this acquisition better. Still, the timing of the deal and the subsequent delay (even suspension) of other partnership talks has left us where we are today. This week's conference call is, without a doubt, the most important one in the company's history. Hedrick must reveal enough information to change the conversation away from the rapidly escalating cost of capital toward the commercialization of scleroderma. We are "Biding the time" until STAR results in 3 months and FDA approval in 12 months to 18 months. Then what? What will be the pace of the rollout to the scleroderma patients?

Investors are betting heavily the results will disappoint; the FDA will not approve; the company will blunder the commercialization, etc. If stem cells were drugs in the eyes of Wall Street instead of just the FDA, the market cap of Cytori would be above $3 billion in advance of the results. The difference is all on Hedrick and the faith he is able to create among investors. Thursday will be quite a show!

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Biding The Time...again. 08 May 2017 07:39 #9289

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Thanks for all the relevant information sharing Franshei. Your optimism in respect of the ease of finding partners for the PSL products, is contagious, but my view has always been that we are dealing with Hedrick et al. I do not think he ever had an issue with the technology from a partnering perspective, but with his high financial demands, which could never be backed with solid Cytori clinical data, but only by anecdotal evidence from others . This has applied the CCT and also will be the case with the Azaya products. So- its still crossing fingers, that he will become more reasonable.

Anyway- on understanding the PSL tech before D-Day- I started reading a bit yesterday and feel this will not be a big deal. I will wait for the CC on Thursday, to see if they come with some simple tech explanation of the synergies, but if they do not (which we normally can expect) I think I can find that out myself.

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Biding The Time...again. 08 May 2017 08:20 #9290

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I think CYTX is very, very lucky to have convincing clinical activity in scleroderma and Raynaud's, as well as Japan as an outlet for celution 800 and BARDA as a r/d launch pad for iv dosing and CTX2 (new IDE needed for Raynaud's using CTX and possibly IV dosing -but pivotal clincals would be very short, because they are mostly 4 months duration). Kerastem is also lucky to have the alopecia indication to go forward. (Niche markets)

I think the old stem cells technologies (allo and auto) think here and elsewhere (first generation) are coming to a close. From hind sight, I think all earlier pursuits in cardio indications and strokesand others (big indications) are hitting a stone wall.

Without a major change in r/d, CYTX cannot go forward. This is why, I think, the AZA acquisition is important.

Back to Liposomal technology. I have only been in clinical r/d and registration, not in basic sciences.

Background, I headed the Ambisome clinical project and filed the IND for MitoXtra, and I had given one week to go over the Jensen IND/Master for their liposomal technology in Belgium (my notes were summarized for filing with the FDA). I have also worked with Israel Chemicals on Microbubbles.

The concept of drug encapsulation (but not for living cells) for target drug delivery is actually an established science. Early on this encapsulation encountered serious doubts (20 years ago), till it was proven by radio tracer technique.

I doubt Hedrick will tell us what is the secrete weapon he is making at this time. But, here is my speculation.

Harris says the San Antonio site can be expanded to do work relating to CYTX's current business -something to do with scleroderma and Raynaud's (I think that if CYTX is good in just one area, the whole company can be very successful). Yet, the San Antonio site (just like Lypomed's site in Orlando) is really devoted to oncology. Cytotoxic agents cannot be mixed or crossed over to other drugs. Then, how can cell free, druggable, non carcinogen be manufactured in San Antonio?

The answer can be very simple! This is only my guess.

Cytoxan and stem cells local therapy have been used in combination for years for advanced illness stage (Northwestern Medicine and U. of Michigan and Johns Hopkins). But, cytoxan is toxic and it has caused secondary tumors and early death.

Yet, liposomal encapsulated cytoxan (it will be a new drug, no one is in this r/d, because cytoxan is cheap and commonly available) can be used in scleroderma/Raynaud's patients without all the known toxicities.

The combination of Habeo and liposomal cytoxan can be a very powerful weapon for the hands and related organs, up to end stage illness.

If my speculation is true, then the potential business partner would be a pharma with an ongoing oncology business and interests in medical device,

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Biding The Time...again. 08 May 2017 09:05 #9291

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*** Then what? What will be the pace of the rollout to the scleroderma patients?***
Exactly

*** I do not think he ever had an issue with the technology from a partnering perspective, but with his high financial demands, which could never be backed with solid Cytori clinical data, but only by anecdotal evidence from others ***
Certainly the latter part of this statement a issue imho.

***(Niche markets)***
I know I heard this term somewhere before....LOL !

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Biding The Time...again. 08 May 2017 10:43 #9292

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If CYTX would make liposomal cytoxan as part of the whole scleroderma strategy, the r/d and clinical development should be quite simple and quick.

Dr. A Raman formerly with Georgetown Lombardi and a pioneer in liposomal technology told me that cisplatin is the most difficult encapsulation -because cisplatin is so reactive that it tends to bind with everything that it is in contact. Cytoxan encapsulation should be really easy. The clinical should also be straight forward because cytoxan is one of the most common cytotoxic agent. All CYTX needs to do is to find a most common chemo regiment and do a comparative study with cytoxan in one arm and liposomal cytoxan in the other - side effects would be the key in this comparison. Of course, prior to clinicals, preclinical comparative tox should be performed.I assume all reagents and chemicals are so-called commonly recognizable types to get through the FDA.

FAS, afterthoughts which would interest you!

Re Hedrick's secret Nanotech Regenerative Medicine.

The key word here is BLEOMYCIN! Bleomycin was my first clinical project at Bristol-Myers, before my platinum projects (I wrote the first comprehensive review on the platinum analogs and filed the first INDs).

One of the headache re handling the bleomycin clinicals is constant weekend calls re bleomycin side effects - over dose and lung fibrosis. Now, this type of side effect is becoming CYTX's clinical focus to conquer -scleroderma, Raynaud's and lung fibrosis. Belomycin is used to induce all the above in animal model and treatment of this kind of illness is the focus here.

There are experimental cellular treatments (not cells, but cellular components) and drug delivery can be a problem - liposomal nanotech maybe the answer 1?

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Biding The Time...again. 09 May 2017 04:10 #9294

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franshei wrote: The answer can be very simple! This is only my guess.

Cytoxan and stem cells local therapy have been used in combination for years for advanced illness stage (Northwestern Medicine and U. of Michigan and Johns Hopkins). But, cytoxan is toxic and it has caused secondary tumors and early death.

Yet, liposomal encapsulated cytoxan (it will be a new drug, no one is in this r/d, because cytoxan is cheap and commonly available) can be used in scleroderma/Raynaud's patients without all the known toxicities.

The combination of Habeo and liposomal cytoxan can be a very powerful weapon for the hands and related organs, up to end stage illness.

If my speculation is true, then the potential business partner would be a pharma with an ongoing oncology business and interests in medical device,


I do sincerely hope that you are totally off-base here. Stem Cell Transplants as they are called , is what you seem to be talking about and that is done mainly against blood cancers, like leukemia and severe auto-immune disorders like scleroderma. Dr. Burt at Northwestern is well known for many many years now with this procedure and several other centres on the globe are are doing it and has been developed by the practice of medicine in the past 40 years or so. Presently there are about 70-100.000 SC transplants annually on the globe by my knowledge.

They wipe out or "kill" the marrow with chemo stuff (like your Cytoxan) and than re-set the immune system by injecting stem-, but mainly hematopoietic cells. This works better I think with marrow cells than fat cells, since marrow makes the RBC´s et al. Although I have a paper on my disk which describes a successful GvHD SC transplant case of a young person where the re-setting of the immune system was done with ADRCs.

Actually Dr. Burt has at present the negative "spotlight" on him- he does "light transplants" or "non-myeloablative stem cell transplants" now on MS- patients, which show quite some promise, but has the patients pay dearly for the treatment (Paul Knoepfler is writing about it). Anyway- here is an older article on Burt- HERE

Whatever- I feel this is all old tech, which is not worth pursuing. I hope the PSL tech will carry cells or vesicles to the site of injury and not toxic junk.
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Board moderator and Site-owner. I still regret the day I started analysing the prospects of MacroPore (now Cytori) back in 2004- a left-over from the tech-bubble at that time from the century change in my portfolio- and became addicted to Cytori´s fat cell technology. :cry:

Biding The Time...again. 09 May 2017 07:16 #9295

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I hope that I am wrong too, but the more I think about Lipo Cytoxan, in line with recent activity of Martin Shkreli and others (who have made big money resurrecting old techs), the more I think that Lipo Cytoxan would make SOME good sense for CYTX. Here in Chicago, there is new micro pharma (started by x Abbott people) doing what Mylan and Shkreli are doing - doing extremely good business in a very short time (within 2 years).

Actually, lipo Cytoxan's side effect profile may be drastically different/lower from cytoxan. (Cytoxan has been used in scleroderma and it is currently a common practice - but it is too toxic and lipo cytoxan could be turn things around here.) If CYTX would make lipo cytoxan, the establishment of a new chem lab by CYTX in San Antonio (see Harris interview) makes sense.

Besides, lipo cytoxan could potentially generate multi, multi million dollar annual revenue for the company,based on low tech and easily FDA approvable pathway (including very short preclinical and clinical development time). Ronald Martell, our new board member, may have been brought in for a good reason. Lipo Cytoxan may have a broad sales and marketing appeal to attract a big pharma partnership which may include Habeo (Habeo may not be enough for a big ticket deal and big upfront payment.)

Hedrick is a plastic surgeon and I think he may copy some of the attempted BOTOX clinical developmental attempts here.

Just my very humble opinion.

Afterthoughts: If Liposomal CYTXAN is indeed our new secret weapon, I dare to say (many apologies for another out of box thinking) that our PPS will recover (to $ 15 = $ 1 presplit).

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Biding The Time...again. 09 May 2017 07:50 #9296

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***Afterthoughts: If Liposomal CYTXAN is indeed our new secret weapon, I dare to say (many apologies for another out of box thinking) that our PPS will recover (to $ 15 = $ 1 presplit). ***

OK, fine, but why doesn't the company lay out their plan ?
Especially when they need/needed cash so desperately ?

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Biding The Time...again. 09 May 2017 07:58 #9297

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OK how this would work clinically with Liposomal Cytoxan.

There many stages in scleroderma illness progression.

Raynaud- Low cost treatment. IV dosing of Habeo, CTX2. Plastic surgeon's office, because of liposuction. Big business, 20 times scleroderma.

Moderate scleroderma-Habeo.

More than moderate, severe by not end stage scleroderma, involving the lung (limited)- lipo cytoxan induction, then iv Habeo.

CYTX will be the one game in town for scleroderma.

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Biding The Time...again. 09 May 2017 08:10 #9298

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Franshei,

What do you think about the liposomal delivery of allogeneic ADRCs for those scleroderma patients who are too thin to undergo liposuction? I was told that is part of the synergy.

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Biding The Time...again. 09 May 2017 08:25 #9299

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Most liposomal technology would not allow encapsulation of cell size particles. Besides, there is a lyophilization step in the manufacturing process, which could destroy the cell or fragments of the cell encapsulation.

Besides cytoxan, we can try methotrexate, which is also used in arthritis - safe in low doses.

Whatever is going on now, I think CYTX is cooking something which will be great for the company and the stock price. I think one should be patient here. Hedrick will not reveal the secret unless he has to - there is furious competition coming from somewhere.

I think the main reason that U of Michigan did not enroll any scleroderma patients in the STAR trial is - they see a lot of more advanced patients and cytoxan has to be used. To make the story complete, I think Habeo needs lipo Cytoxan.

DOV, on the issue of skinny women, I think it has to do with crytofresh and crytoreserve issues - a separate issue.

CytoExtra (my new name for lipo cytoxane) may have a lot mileage, if it indeed it is the secret weapon. The potential market size is big (more than $ 100 million a year). This is what Joe Rubinfeld (x AMgen COO and founder of SuperGen and formerly a VP at Bristol) with MitoExtra.

Please remember when we started at Bristol Lab in the 1970s, the annual sale was only $ 100 million. Stan Crooke (founder of Isis and current CEO) brought cisplatin to the market and the first year sale was over $ 100 million - that was in the late 1970s. We paid only $ 7000 for the licensing in of cisplatin from NCI. Stan Crooke was only 35 when he was made VP of Oncology. I told Tiago that we have to learn from my xboss to be dynamic and ruthless to get things done at CYTX. Bashers and short sellers are everywhere and Stan Crooke as well as John Kapoor had been attacked and but they overcame these attacks.

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Biding The Time...again. 09 May 2017 09:19 #9300

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In the early discussions of the Azaya deal I found this article from 2014 which I found interesting.
Maybe franshei can comment as well on its possible relationship to what he invisions with the Cytori/Azaya combo.
austinpublishinggroup.com/clinical-pathology/fulltext/ajcp-v1-id1001.php

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Biding The Time...again. 09 May 2017 10:12 #9301

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DOV wrote: Franshei,

What do you think about the liposomal delivery of allogeneic ADRCs for those scleroderma patients who are too thin to undergo liposuction? I was told that is part of the synergy.


I think I already asked before, but prefer to ask again- that person was talking cells right? And not extracellular matter or vesicles. Was it Girao again or somebody scientific?

Anyway- I do share Franshei´s concern on lysis (cell death) upon encapsulation, I do know ADRCs can be brought in either a hydrophobic state (water repellent) or hydrophilic state (water binding), which seem to be important for being transported in a liposome membrane system, which relies on the vascular system for transport (which is water based). I do think the ADRC size is small enough though.

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Board moderator and Site-owner. I still regret the day I started analysing the prospects of MacroPore (now Cytori) back in 2004- a left-over from the tech-bubble at that time from the century change in my portfolio- and became addicted to Cytori´s fat cell technology. :cry:
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