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What is the future value of NBS?
It is highly likely that the Preserve P2 results will be positive for the efficacy of NBS stem cells for cardiac disease adding great value to NBS.
Regardless whether or not BAX makes a buyout offer for NBS, the NBS subsidiary PCT now has over 100 clients. Within five years PCT earnings will start to increase geometrically and be in the tens of million dollars annually.
While the Treg and VSEL technologies are yet unproven, major centers (e.g. Harvard and UCSF) are exploring these avenues. Any one of these technologies if subsequently proven followed by product approval could lead to humongous sales.
Regarding other possible competition other than BAX, ATHX is also involved in stem cell studies with its Multistem (r) product for acute MI and stroke patients. It is my opinion that ATHX has encroached upon NBS patent technology. It would be a frivolous waste of money for NBS to challenge ATHX at this time. NBS patents for its stem cell technology are overwhelming.
ATHX has another problem. Its IBD studies with Pfizer will probably fail because the underlying autoimmune process has not been corrected. Giving stem cells to patients with IBD is analogous to giving transfusions to aplastic anemia patients. As long as the underlying pathology remains uncorrected, repeated transfusions remain necessary. NBS has not fallen prey to trying to treat an autoimmune disease.
In my opinion, Mesoblast and Osiris will not be significant competitors for treating heart disease. Down the road PSTI with its PLX placental derived cells may be an important competitor but currently it is interested more in PAD and other areas.
Cytori (CYTS) may find that the need for its Celution One instrumentation limits its competitiveness in treating heart disease. This machine extracts a clinical grade mixture of adipose derived regenerative cells (ADRCs) but the price for the equipment will probably limits its availability except at regional centers.
If NBS maintains a future lead in treating cardiac disease cost effectively with stem cells, it will be a multi-billion dollar company if it is not bought out first.
A Dream
I had a dream that woke me up last night that CTSO would merge with New Health Sciences, a private company that is the maker of Hemanext a blood purification device. Through the merger New Health Sciences would have an exchange listing, the technologies would merge as well, and the combined companies would more or less control the important niche maintaining blood transfusion safety.
http://newhealthsciences.com/our-company/
CTSO’s other products would be a separate division to that of Hemanext in the combined new company.
It was a nice dream and I went back to sleep peacefully. I have absolutely no personal knowledge one way or the other whether or not CTSO management is interested in or has contacted New Health Sciences.
UNEXPECTED ANNOUNCEMENT OF CE MARK APPROVAL FOR HEMODEFEND??
One surprise could be an unexpected announcement of CE Mark approval for HemoDefend similar to the unexpected announcement more than two years of CE Mark approval for Cytosorb. That certainly would be a positive. Primarily safety would have to be shown for approval. Sales staff could then push HemoDefend and Cytosorb and overall sales could improve.
LESS DILUTION AT THIS POINT??
With the price per share around $0.10, the exercise price for LPC, there will be less dilution mathematically and LPC will have very little reason to sell into the market as long as the price per share stays around $0.10 the price at which LPC purchased shares. Perversely CTSO may have more incentive to go back once again for LPC financing.
HemoDefend Product Brochure
This is a classy presentation that should create interest.
http://www.cytosorbents.com/pdf/HemoDefend_Product_Brochure_2013.pdf
There is insider support.
Someone or a group somewhere is giving support
at a price of around $0.10 and this resistance level of around $0.10 is encouraging. Maybe the support is being generated indirectly from CTSO officers although insider purchases do not support this speculation. What does seem clear thought is that the recent officer financing of about $1 million constitutes for all intents and purposes significant insider buying.
JDolby, you could add of course a partnership for Cytosorb
with significant money up front as another announcement that would move the stock.
In addition to the concerns you cited, finances have become so threatened at CTSO that now there seems to be peer pressure among its officers to advance money. Will the last tranche of about one million be followed by another officer generated loan? So far the goodies tossed to officers giving them incentives to put more money into the pot have been moderate in degree, even reasonable. But what happens if there is another tranche within a few months where the goodies become exorbitant? What if absolutely no outside financing materializes? Can Chan count on going back to company officers for another loan? What follows if Cytosorb sales are unsatisfactory? Without a partnership or sales materializing this company seems doomed.
On the other hand, it is reassuring that if we investors go down, there will be some very unhappy officers who will surely be losing a lot alongside of us. What do the officers and insiders know that we don’t know?
Personally I do not believe CTSO officers would have become involved in a one million dollar personal loan without justification and therefore I now strongly suspect a partnership either for Cytosorb or HemoDefend is around the corner.
“Interleukin-6 at discharge is an independent predictor
of all-cause mortality in patients with sepsis. Compared with IL-6 at admission, IL-6 at discharge better predicts all-cause mortality.”
http://www.ncbi.nlm.nih.gov/pubmed/23896015
Is it not therefore possible that by lowering IL-6 prior to discharge mortality will be reduced in patients with severe sepsis? How speculative is it to surmise that Cytosorb is lowering IL-6 and improving survival for severe sepsis patients in the EU?
Pessimism seems to be at a peak. Is it time to buy?
Jul 26, 2013 4:28 PM: “There is a big problem when people here on this message board report more news than the CEO Chan. He is deliberately holding back information from shareholders. He is deliberately holding back information to keep the pps down and to mock us investors.”
Jul 26, 2013 2:32 PM: “Chan should either start acting like a CEO instead of a MD presenter or be replaced immediately.”
Friday, July 26, 2013 7:02:53 PM: “Chan just needs to do a better job of getting the success stories out there. We keep hearing about all the investigator led studies, but nothing about the indications. What is the secret? Let the investors know what is going on. I give Chan an F as it relates to investor communication.”
Critical comments like those above are reaching a crescendo on message boards perhaps indicating a bottom on a contrarian basis in the price of a little over $.10 per share for CTSO.
Commentators perceive the risk to investors to be that corporate parsimony in giving out meaningful information, the reluctance so far to structure and consummate a major partnership and the incessant need to initiate one study after another while not having the funds to start and finish a FDA study could lead to ongoing pps deterioration. Furthermore, if the pps should fall below $.10 there could easily be a cascade downward in price. Corporate malaise could follow with one key figure after another resigning because of the lack of progress in share appreciation.
But the long overdue announcement of a partnership and more openness will come surely, and there are strong positives.
Even if thinking to a major extent is still predicated to a large extent upon being piggy and eating the whole pie, CTSO has taken on Chris Cramer, who is experienced in structuring partnerships formerly with J&J.
Assertions that initial EU studies were inconclusive are unfounded and/or disingenuous. ”In the high cytokine level group, 28-day mortality (28 days is widely accepted as the standard time mortality endpoint in sepsis studies) was 0% in the CytoSorb cohort versus 63% in the control cohort (statistically significant p=0.03, n=14: 6 treatment / 8 control),” summarized Zacks.
Regarding HemoDefend Zacks wrote, “The polymer beads meet ISO 10993 standards for biocompatibility, hemocompatibility, genotoxicity, cytotoxicity, acute sensitivity and complement activation and can therefore directly contact blood for extended periods of time.” These attributes are truly amazing!! The target markets for HemoDefend could be half of the 150-200 million transfusions given worldwide each year. HemoDefend is a device that will be marketed someday.
If dosing studies are inconclusive, that finding could easily be construed as positive. http://investorshub.advfn.com/boards/read_msg.aspx?message_id=9000328. Entirely too much negative emphasis is put on delays in reporting the results of dosing studies or that inconclusive results would be damaging.
The need for a major partner has become so great that assuredly there will be one announced before the end of 2014 for HemoDefend or Cytosorb, or both. Details of how a FDA study would be conducted are still pending but likely to be announced as well before the end of 2014. If these announcements materialize a reverse split will follow that will certainly IMO lead to major appreciation in the pps. http://investorshub.advfn.com/boards/read_msg.aspx?message_id=90351156 It is not a matter of if there will be such developments, but when.
Good discussion of reverse splits
http://seekingalpha.com/article/1572642-neostem-great-reverse-split-activity-but-whats-next?ifp=0
So why bother with such a study?
Briefly it would seem the Greifswald study is measuring differences in the need to use the hypertensive agent Norepinephrine six and 12 hours after the start of Cytosorb compared to the initial dose given at the start of Cytosorb adjunctive treatment for septic shock. There is a broad age range of patients between 18y/a to any older age in a very small sample size of 20 patients. What goes unsaid is why Norepinephrine was chosen as the hypertensive agent when there are alternatives, many better than Norepinephrine, and why was such a broad range of ages used in the study? Furthermore, at what hypotensive levels would Norepinephrine be used? What would be the controlling factors in determining whether or not Norepinephrine would be used and if used at what doses? If patients with only refractory shock are being included, by definition these patients are not responding to any hypertensives. At best with such a small sample of just 20 patients and these and other questions going unanswered in a single arm uncontrolled study from a number of inclusion criteria, the structure of this study seems very questionable. The likelihood of any statistical significance being shown is unlikely. So why bother with such a study?
Some of the problems Dr. Kosanke may have difficulty addressing effectively is that with 80 or so KOLs all designing studies that they are for the most part self-funding, it is highly likely that many of these studies will not be coordinated and/or designed well.
Incidentally, Dr. Kosanke obtained his PhD from the University of Greifswald, where he became an Associate Professor.
NO BIG DEAL IF DOSING STUDIES ARE INCONCLUSIVE
If the dosing studies show inconclusive evidence that one protocol or another is better, that would confirm that Cytosorb has wide applicability. There would be little need then to initiate 24/6 v.s. 6/24 protocols or some variation thereof for serious sepsis if there is no statistically significant difference between protocols. If this is the case, please tell us DC. Such an announcement would really not be bad news. Please tell us what is going on with the dosing studies. Could a theranostics study have been started this year, assuming financing was available, for Cytosorb if the dosing studies were inconclusive?
An Update to Ping’s Half Year Review
Half Year Review:
Trying to get a new medical product on the market is not for the faint of heart or the impatient with limited funds. The morass of regulations precludes easy access to markets for a new IDE. Time to approval can stretch out interminably as one modification after another seems necessary and yet another study is started. A simple study that leads to early representations that initial results will become available soon confounds the managers when initial results are delayed month after month because they are not as good as expected or are confusing and non-conclusive statistically. In the excitement of exploring multiple uses for the new product, multiple independent studies are started. Overlapping responsibilities lead to more confusion and questions as to who will do what and when he or she will do what the designers thought someone else would do. A CFO resigns in disgust and newly hired IR firms prove to be ineffective. So it becomes obvious that there needs to be a coordinator in the country where multiple studies and an increasing number of investigators all wanting a piece of the pie are competing academically. A coordinator is appointed, but be careful some warn.
Coming up (We truly hope not) “There is nothing to fear but fear itself.”
The multiple designers insist upon maintaining hegemony. After all they are independent KOLs. The newly appointed research coordinator Herr Doctor Korsanke regrettably proves ineffective when compliance from critical leaders becomes limited. Results remain confusing or non-conclusive statistically. Disillusioned, exiting investors and foreign researchers arguing they were misled file suit in Germany and in the U.S. Litigation expenses balloon. Funding becomes unavailable as LPC backs out finally when it refuses to buy another 45 million shares because the pps is below $10. More litigation ensues. The pps plummets as KOLs exit when funding becomes insufficient. Pessimism replaces optimism.
Investors hope and a belated realization
Our prayer and hope are that the results for what was originally represented as a simple study, a so-called dosing study, for the new medical product Cytosorb will finally be announced after many representations that initial results would be available late last year. Investors and management finally realize that inconclusive results do not indicate bad news necessarily when someone argues and management wakes up to the fact that it is a positive development indicating wide applicability when no significant difference can be demonstrated between 24/7 versus 6/24 Cytosorb applications or some variation in treatment applications thereof.
Sad Reflections
It is a sad reflection upon CTSO managers in the eyes of many investors that some dosing study updates were not given last year. It is so, so sad that when some investors suspected a lack of integrity the reaction of managers was to clam up even more. It is even sadder that good news has led repeatedly to a fall in the price per share because in part corporate announcements were incomplete.
What is desperately needed
More openness is desperately needed.
A corporate review of the benefits of being more open with investors and quarterly SHLs are long overdue. An investor website where DC could give feedback to all rather than replying to individual Email writers would help console investors and the price per share. It would ease DC’s psyche further if his need to reply to individual email investors abated in conjunction with more corporate openness and SHLs.
The rhabdomyolysis study
being financed by the U.S. Airforce is good news, but not a sure path to success. It simply may not be a quick path to FDA approval of CytoSorb. Rhabdomyolysis occurs with trauma and is distinctly different from sepsis where cytokines are elevated. The populations being studied will presumably be of young air force age and not an elderly group 65 years and older previously identified as being at high risk with severe sepsis. While CytoSorb may be proven effective in such a study in removing muscle breakdown products including myoglobin, it is speculative to assume there will be a proven increase in survival with CytoSorb usage in trauma when myoglobins are elevated or for that matter when not elevated. There is nowhere near the sure positive outcome one would expect with CytoSorb improving 28 day survival in an elderly 65 y/a population with severe sepsis.
An assumption
by many has been that the pivotal IDE trial would be in the U.S. Since CTSO has about 60 KOLs with more coming on monthly in Germany and since the FDA accepts data from studies done in Germany, it is entirely possible that the pivotal IDE trial would be done in Germany rather in the U.S. after dosing studies are completed.
If indeed a revision to the original IDE trial already approved has been filed as Ping suggests because of the revised MedCity article that strongly implies the IDE revision submission incorporated dosing study results and sought permission for the pivotal study to be done in Germany.
FDA approval of the revision would be exciting news because it would confirm more or less that dosing studies have been positive and were incorporated into the revised submission. The absence of a denial within 30 days of the application for a revision of the original IDE trial grant is in itself confirmation as Ping points out.
A pivotal IDE trial in Germany could be easily and quickly done with perhaps as few as 60 patients and just as importantly CTSO has the financial means to do such a study. If my speculations are correct, an announcement could be soon that a pivotal IDE study will be done in Germany.
If CTSO plans subsequently to the pivotal IDE study to do the premarket study in the U.S. costing CTSO estimates of 8 – 12 million (that seems excessively conservative to me), it will have to raise money somewhere else. Hemodefend remains the best bet for funding that would enable CTSO to garner all the upside potential from Cytosorb. Makenlight has pointed out the incidence of packed RBC transfusion reactions.
Pressure is building in the medical community for a device to limits such reactions. HemoDefend to the rescue he said, and he is right.
It would seem a multiple of positive news announcements are coming in the next six months.
Blood Purif. 2012;34(2):164-70. doi: 10.1159/000342379. Epub 2012 Oct 24.
Continuous hemodiafiltration with a cytokine-adsorbing hemofilter for sepsis.
Hirasawa H, Oda S, Nakamura M, Watanabe E, Shiga H, Matsuda K.
Source
Department of Emergency and Critical Care Medicine, Chiba University Graduate School of Medicine, Chiba, Japan.
Abstract
Since the introduction of the new pathophysiological concept of pathogen-associated molecular patterns (PAMPS) and alarmins, endotoxin has been recognized as only one of the PAMPS. It is widely accepted that hypercytokinemia plays a pivotal role in the pathophysiology of sepsis. Many kinds of blood purification modalities have been proposed as a therapeutic tool against sepsis, including high-volume continuous hemofiltration whose efficacy has recently been questioned. We report that continuous hemodiafiltration (CHDF) with a cytokine-adsorbing hemofilter (CAH), such as polymethyl methacrylate hemofilter and AN69ST hemofilter (CAH-CHDF), can remove many kinds of cytokines and has been very effective in the treatment of severe sepsis and septic shock. Based on the understanding of the recent pathophysiology, we suggest that CAH-CHDF is an alternate therapy to direct hemoperfusion with endotoxin-adsorbing column in the treatment of sepsis.
Copyright © 2012 S. Karger AG, Basel.
Long-range Strategic Planning
Cytosorb is the crown jewel of CTSO.
What are the implications for long-range strategic planning? What follows is in part speculative but also in part factual.
The crown jewel is not HemoDefend, ContrastSorb, or any of the other products currently developed or that will be developed. It is these products that will be “monetized” to use a Chan word through partnerships that are being actively explored.
My feeling from listening to interviews and reading releases is that Dr. Chan would prefer not to monetize Cytosorb at this time through a development partnership. Distributor partnerships are a different matter and will be actively sought.
It would be interesting though if a major pharma said that they did not really care about dosing studies being completed because of delays in reporting and pushed for starting FDA theranostic studies, in effect jump-starting the road to Cytosorb approval in the U.S. Would that be a gamble? Certainly, but the odds of success would be high and on a discounted cash flow basis making various assumptions the returns would be greater than waiting for the completion of dosing studies with further seemingly endless studies and and in effect “study creep.”
It may well be that following the completion of the dosing studies, other studies would be done possibly in Germany and that these studies involving small numbers of patients, less than 60 – 70 for example, would be self-funded. Since the FDA readily accepts studies done in Germany, these additional studies would constitute in effect in total a pilot study before a PMA or 501(k) pathway (which path would be followed is still not clear) for FDA approval that would require further studies. FDA trials funded by CTSO would not be feasible financially in the U.S. today with current estimates of 8-12 million dollars in costs, but could be entirely feasible after monetizing one or more other products.
Once another product than Cytosorb is monetized, predictably the pps of CTSO will increase dramatically. At that time dilution will lessen. It is really that simple. The strong impression from reading new releases and listening to interviews is that a partnership for a product other than Cytosorb is being actively sought and will be announced this year.
The catalyst will be in part through increasing Cytosorb sales, but also increasingly likely through the announcement of a partnership (possibly the Red Cross) for HemoDefend. With the aegis of the Red Cross or a big pharma, the studies leading to approval of HemoDefend are likely to be rather rapid. It is likely that HemoDefend could be approved in the U.S. before Cytosorb. With Chris Cramer on board the execution and design of partnerships that are fair to CTSO is ever more likely.
At this time remaining questions may be mostly medically technical before a partnership for HemoDefend can be announced. For example, are any of the significant bloods clotting factors being removed by HemoDefend? Obviously if clotting factors are removed, the HemoDefend protection would constitute anticoagulation and replacement of those factors might not be feasible except by giving fresh plasma. That would be self-defeating. Are there any toxins in a broad sense that are being left after HemoDefend protection? These laboratory analyses can be done with bovine blood as well as with human blood and are mandatory before any partner would commit.
Once significant evidence has accumulated that HemoDefend is safe through laboratory studies, clinical human studies will be done to prove safety.
Since the ratio of absorptive area to the weight of Cytosorb beads is around 20%, a reasonable question is whether or not there will be “design creep” in improving absorptive ratios. If for instance an improved Cytosorb emerges, that would affect what product would be used in clinical studies. However, if the sizes of Cytosorb beads are decreased so as to increase their proportionate surface areas, a significant problem of hemolysis can occur following the release of the higher perfusion pressures necessary to maintain blood flow through the modified Cytosorb device now having a higher perfusion gradient. “Design creep” is therefore extremely unlikely IMO. If this analysis is correct, there are further implications, namely R and D for an improved Cytosorb will be less.
If sales of Cytosorb reach a point where the present production facilities are inadequate (what a delightful problem that would be), it is likely that the present facilities could be duplicated at minimal cost nearby thereby protecting proprietary information.
The days of ongoing financially disruptive dilution are coming to end through increased Cytosorb sales and partnerships for HemoDefend and other products waiting to be monetized.
http://seekingalpha.com/article/1400171-why-royalty-and-milestone-partnership-dynamics-imply-trovagene-could-triple?source=email_stocks_and_sectors&ifp=0
"a partnership with an established company can do wonders both in terms of reaching profitability and the outlook/valuation for a biotech startup. The benefits are clearly demonstrated in companies that have entered key partnerships in the past year. Notable examples include Organovo (ONVO.PK), Endocyte (ECYT), and Qiagen (QGEN)."
In spite of the DOW reaching highs of around 15,000, CTSO is still languishing around 11-12. Cramer would be very much appreciated if a partnership or partnerships could be structured to expedite development and marketing of some of the products.
Taken from Early Induced Innate Immunity by Makenlight, "Cytokines called chemokines (def) are especially important in this part of the inflammatory response. They play key roles in diapedesis -enabling white blood cells to adhere to the inner surface of blood vessels, migrate out of the blood vessels into the tissue, and be chemotactically attracted to the injured or infected site. They also trigger extracellular killing by neutrophils."
Cytokines play important roles in combating sepsis. It is not unlikely there could be critical cytokine levels for tackling sepsis and that removing too many cytokines with Cytosorb could be injurious.
More about nano sponges, this time from Scientific American.
Tiny Sponge Soaks Up Venom in Blood
http://www.scientificamerican.com/article.cfm?id=tiny-sponge-soaks-up-venum-blood
Please remember that almost every technological development becomes obsolescent sooner or later.
Nanosponges could soak up deadly infections like MRSA from your bloodstream
http://www.theverge.com/2013/4/15/4225834/nanosponges-kill-deadly-bacteria-mrsa-clinical-trial
Injecting humans with nanosponges could be a bit risky, although without studies who knows. But one wonders about extracorporeal usage of nanosponges placed in cartridges that could be hooked up in tandem with Cytosorb cartridges. DARPA might be interested.
Expanding upon the Kaiser versus Pfizer case,
it should be clear that using Cytosorb for every condition where cytokines are elevated carries a potential for litigation. This would be especially true in the U.S. where in general SOC employing a medical device or drug is for a specific use. Because of the precedent now that there can be recovery of costs against the manufacturer for off label usage, some practitioners will feel constrained in prescribing off label usage. Manufacturers must be more careful in how they advertise.
"The jury found that Pfizer had marketed Neurontin for bipolar disorder, migraines and neuropathic pain, none of which had been approved by the U.S. Food & Drug Administration." The court ruled that Pfizer had engaged in fraudulent advertising and imposed a hefty criminal fine. There will be appeals that I strongly suspect Pfizer will lose, and there will be challenges in the courts for physician off label usage that is unsuccessful.
Cytosorb usage for all medical conditions where cytokines are elevated is inappropriate in my opinion even in the EU where broad approval has been granted for conditions where cytokines are elevated. Until specific trials are designed and carried out for Cytosorb usage for specific mental health or other medical conditions there must be caution concerning Cytosorb employment. Without question this assertion would be especially true in the U.S.
Speculation that Cytosorb may be employed safely and without legal recourse for mental health conditions and a host of other conditions where cytokines are elevated is rank speculation until specific trials are completed and there is agency approval.
Court Upholds $142 Million Verdict Against Pfizer Inc. Over Neurontin
http://www.biospace.com/news_story.aspx?StoryID=292378&full=1
http://www.reuters.com/assets/print?aid=USBRE93303R20130404
http://www.reuters.com/article/2013/04/04/us-pfizer-neurontin-idUSBRE93303R20130404
Do you not think that the off label usage in the US of any medical product has potential liabilities? Is it not also reasonable that at some juncture a similar ruling may take place in the EU? What do you think would happen to Cytosorb sales if off label usage were constrained because of such a ruling? Do you really think that Cytosorb usage for any condition where cytokines are elevated is by lasting, unchallenged definition not off label usage? Do you really think that Cytosorb usage for any condition where cytokines are elevated will prevail if label usage becomes constrained to specific conditions such as sepsis, SIRS, MOF, etc.? I suggest this assumption that Cytosorb has obvious widespread application to any condition where cytokines are elevated carries potential legal risks whose ramifications are clearly unknown at this juncture. Meanwhile, I remain very positive about EU sales accelerating because of wide spread applicability of Cytosorb to any condition where cytokines are elevated. Nonetheless, I am concerned that there could be more constraints as to Cytosorb usage at some future juncture in the U.S. than are currently in place in the EU. Such constraints would inevitably demand multiple studies for specific conditions starting at the earliest I suspect 3-4 years from now.
COMPETITION FROM OTHER DEVICES IS INCREASING:
A simple concern is that CTSO has not proven the superiority of Cytosorb over many other hemofiltration devices for sepsis. Will the Wyss device whose announcement today that a DARPA award was granted be proven eventually as the best device for sepsis?
http://medicalxpress.com/news/2013-03-wyss-awarded-darpa-advance-sepsis.html
Will AEMD technology be eventually chosen over CTSO technology in combination with Wyss technology for treating sepsis? The opsonin coating used in the Wyss device strongly suggests AEMD is involved in the design of the Wyss device. Is CTSO being left out in the design of the Wyss device?
Let’s not forget other devices for sepsis either.
ExThera Medical Corporation could be a potential competitor to CTSO.
Aethlon Medical, Inc. (OTCBB: AEMD.OB - News), the pioneer in developing selective therapeutic filtration devices to address infectious disease, cancer and other life-threatening conditions, has announced that it has established a Sepsis & Inflammation Scientific Advisory Board to provide guidance on the development of new therapeutics, including a device to reduce the incidence of sepsis in combat-injured soldiers being advanced under a contract from the Defense Advanced Research Projects Agency (DARPA).
Delcath is in the final stages of preparing the New Drug Application (NDA) filing for its proprietary chemosaturation system with the first-generation hemofiltration cartridge.
"Nephros received a final decision letter from the FDA for the company's 510(k) submission which stated that the FDA could not reach a substantial equivalence determination for the company's hemodiafiltration (HDF) system."
Other first tools that might be used for sepsis and that can still be called membranes range from AN69 Surface Treated (ST), SEPTEX, polymethylmetacrylate, to Oxiris that can still run with a CRRT device. Polymyxin B is still a kind of membrane although it has a larger surface, but it can run in a hemoperfusion system and is also much more selective for endotoxins.
Cytopherx products are custom, patent-protected configurations of commercially available hollow fiber dialysis filters that are used in a proprietary manner to sequester and deactivate leukocytes in the patient’s blood system. The Company is initially focused on acute renal failure (ARF).
Now today we learn there is increased DARPA support for the microfluidic "Spleen-on-a-chip" developed at the Wyss Institute at Harvard University that will be used to rapidly treat bloodstream infections. By coating the inner surface of the channels of the device with SLIPS, blood cleansing can be carried out without the need for anticoagulants to prevent blood clotting.
Is it fair to ask which device for sepsis will be proven most effective and will prevail? Is it fair to be concerned that delaying a FDA study until endless and unreported dosing studies are completed may not be the wisest strategic course for CTSO? Technology moves quickly but not seemingly CTSO that continues its shameful news blackout on dosing studies and painfully slow progress towards proving Cytosorb efficacy.
Ping, standardization is the key to structuring valid dosing studies with sufficient power to show statistical differences between dosing regimens. This is not a statement that requires arcane knowledge to confirm. Without standardization dosing studies may mean little.
All it would take to relieve this concern about standardization is for DC to state simply all dosing studies are standardized. Or DC could give interim results. Or DC could give an update. It entertains me that Dr. Low, who has impressed me as being quite knowledgeable, has in previous messages shared this concern.
I am not in a position to say unequivocally the dosing studies are not standardized or that they are standardized throughout. I just do not know and am simply expressing a concern that could be readily resolved if ever the worrisome news blackout from DC is eventually lifted and he ever so graciously addresses this issue.
Let me turn the screw the other way and ask you why you do not share this concern?
Standardization??? Not so apparently.
On the Yahoo message board Petryandre33 reported his meeting with Drs. Steiner and Chan.
http://finance.yahoo.com/mbview/threadview/;_ylt=AoVBZ2Y2HcHT_Yu2ZMMkNFDeAohG;_ylu=X3oDMTB2OHBjOG42BHBvcwMyMgRzZWMDTWVkaWFNc2dCb2FyZHNYSFJVbHQ-;_ylg=X3oDMTBhYWM1a2sxBGxhbmcDZW4tVVM-;_ylv=3?&bn=ebd8603b-22a5-35e8-aa26-37428fa8fe6a&tid=1363919529166-bda1e2f4-07e5-48ca-8b62-5a602acea9b3&tls=la%2Cd%2C1%2C3
“German physians <sic> are so enthusiastic that they're starting their own investor conducted trials with our filters. It cost nothing to CTSO.” How do we reconcile this statement with Ping's earlier reassurance that all dosing studies were being paid by the company and all studies were standardized?
This first hand report by Petry does very little to allay concerns that all the dosing studies are not being standardized.
Where is the evidence from DC himself that the studies are standardized? Is it possible that results of dosing studies have not been reported because these studies are not being standardized? Why does the news blackout on dosing studies continue? Is it shameful that DC remains silent on this critical issue after repeated suggestions if not reassurances interim results would be given Q4 12?
Petry did confirm that Cytosorb is being used for many indications other than sepsis. I remain very optimistic about Cytosorb despite my concerns as to the reasons absolutely no meaningful results have been given to the best of my knowledge about dosing studies.
The potential markets for Cystosorb usage when cytokines are elevated are far, far larger than the markets for sepsis. The relevant question may be not if Cytosorb is approved for cardiac surgery and all the other surgeries being done at the University of Göttingen, in Göttingen, Germany and elsewhere throughout Europe but when. But recognize that in general physicians will be reluctant to use a device for conditions that have not been specifically approved for that device.
Approaching Cytosorb usage from the standpoint of WHEN broader usage takes place rather than IF clearly points to far, far greater markets than those for sepsis alone. It will be interesting to see if Dr. Quintel is able to push Cytosorb usage into the realms of cardiac and organ transplant surgery at the University of Göttingen based upon Cytosorb having CE Mark approval whenever cytokine levels are elevated. If he does thereby enabling Cytosorb usage to pass through a critical barrier where physicians are reluctant to use a device that has not been approved for a specific procedure, gang buster sales would quickly follow. Very little attention has been given to Cytsorb usage that is not related directly to sepsis and therefore the potential markets many years from now are vastly understated in this context.
In most instances of cardiac surgery an arterial line has already been placed for constant blood pressure monitoring. A CVP line is often in place as well. It would be relatively easy with those portals in place to insert a pump using Cytosorb cartridges to filter out cytokines.
Sooner or later WHEN (and not IF) Cytosorb and other filters capable of filtering out cytokines come into general acceptance in cardiac and other surgeries at least in the EU, CTSO should start to approach its full market evaluation. View this assertion as a note of great optimism.
In the broad context that whenever excessively high levels of cytokines occur Cytosorb can arguably be used according apparently to the CE Mark label. That would encourage of course wide spread usage of Cytosorb for various situations where cytokines are elevated. But has CTSO pushed such usage going beyond the limited usage for just sepsis? If CTSO marketing is being directed towards broader usage whenever cytokine levels are elevated, that may be helpful for overall sales but such usage would contribute little to nothing about dosing studies. I am a little leery of expanding usage to all conditions where cytokine levels are elevated because of possible legal recourse.
If it is true that Cytosorb is now approved for cardiac surgery and organ transplants in the EU that is big news. It is also surprising that CTSO has not made an announcement to the effect if this development is true. I would appreciate further confirmation.
Warren, I think you are quite correct that there would be a speculative selloff following a listing on a major exchange at a price of $3.00 or greater in the absence of FDA approval or strong sales.
Ping, you wrote, “Stopping or cutting back on the dosing study because they don't have enough money is dumb.” Ping, with due respect to you, one of the dumbest actions CTSO could embark upon would be continuing dosing studies in the absence of sufficient funds to carry the studies to completion or if sufficient data is already available.
If the power to differentiate between treatment arms is insufficient to show statistical significance as you suggested is the case without expanding the studies significantly and if only interim data from the dosing studies are needed to submit an application for a FDA trial, surely there is less validity to continuing dosing studies at this juncture when DC repeatedly said interim data would be available and when finances remain critical. If CTSO has the financial wherewithal to continue dosing studies through 2013 or if more than just interim data is needed, DC should update us. We have had no updates from DC in over two months.
As for the dosing studies being standardized, I have still not seen a reference confirming this. Even if CTSO is picking up the entire expenses for dosing studies (I am frankly incredulous that this would be the case), it is quite possible that the KOLs as independent entities who may feel they know best would want to add twists to the studies being conducted at their centers. If DC would only confirm the studies are standardized I would be satisfied, but he has not done this.
The proxy statement today that up to 800 million shares are now authorized seems contradictory to previous speculations that a reverse split would be necessary in order to be up listed to a more major exchange. What in the world is going on?
I am very eager to stop speculating as much as I have been because of the news blackout that has been in place.
Ping, like Dr. Low I do not know for a fact that the dosing trials are standardized. I never said they were not standardized. I only said I did not know if they were or weren’t. If you have a source that affirms they are standardized, like others I would appreciate having it.
Discontinuing the dosing studies might have a great deal of merit. I do understand that all patients in the dosing studies are being treated, but as you yourself admitted the power might not be sufficient to differentiate between treatment arms. “Are they focused on having sufficient power for the dosing study? I dont' think so because they are not comparing treated and non-treated patients.” That is the very point I was making. There may not be sufficient power to differentiate between treatment arms thereby making the dosing studies inconclusive so far. That is not to say that continuing the dosing studies might not lead to statistically different results, but then at what costs?
You also assert that the dosing study data is required for the FDA application. With due respect to you, I dispute that assertion. I am well aware that DC intended to use the dosing studies in making his FDA application, but to assert categorically dosing studies are necessary before conducting a FDA trial is probably not true unless it is DC’s intent to have a SPA like approval for FDA studies beforehand. A well designed and conducted FDA study could be initiated without continuing the dosing studies.
At this juncture it is critically important that the financial wherewithal be in place before continuing dosing studies and initiating a FDA trial. The balance sheet statements suggest strongly that the financial wherewithal is not in place to initiate a FDA study that could cost easily up to 15 million dollars. Just the announcement that a FDA trial will be initiated before 2014 would have a very positive effect on the pps possibly to the extent that self-funding could become feasible.
Sooner or later DC will have to consider discontinuing the studies to the extent CTSO is funding them unless a partner emerges who can provide funding. As I wrote earlier that is not to say that dosing studies financed by the various KOLs could continue. It would be helpful in marketing, etc. if they did. If these dosing studies are not standardized, they will probably have little relevancy anyway.
One of the issues DC may be facing is this very question: If the dosing studies in Germany are not standardized throughout, should CTSO stop funding them and initiate instead a FDA trial with the information at hand that results are apt to be successful as long as the FDA patient population is older than 65 y/a with high cytokine levels and MOF?
In the absence of any definitive results from the dosing studies being announced, it is appropriate to suspect that they have been inconclusive so far. If so, it would also be appropriate to halt dosing studies paid for in part or in whole by CTSO in order to preserve working capital for a FDA trial that would include only patients 65 y/a and older with high cytokine levels and MOF. These are the subgroups where statistical significance was shown in survival at all time intervals including 28 days.
Unless the dosing studies being done at multiple centers in Germany are standardized there seems little point in continuing them at the expense of CTSO. If these centers are paying for their dosing studies, that would be justification for continuing them. A lack of standardization and/or insufficient power could be reasons for inconclusive results.
Discontinuing the dosing studies paid for in any part by CTSO could make a great deal of sense provided a FDA trial could be started sooner than early 2014 as suggested in the last SHL. We should all be concerned if dosing trials are extended through 2013 without further disclosure as to how they would be paid for and without further disclosure by DC of how and when FDA trials would be designed and initiated.
DC has lost credibility because of the news blackout wherein investors are not being informed as much as they should be. At the same time efforts should be heightened towards finalizing working partnerships for FDA trials of Cytosorb and HemoDefend ASAP.
I remain very optimistic about the future of CTSO although I feel strongly DC has been very ineffective in his approach to IR.
What follows if the dosing studies are inconclusive?
The CytoSorb arms for the dosing study trials are reported to include a 24 hour continuous usage arm that lasts for 7 days, and a 6-hour per day arm that continues until the patient experiences improvement in organ function. Each CytoSorb column lasts for approximately 6 hours, and due to the self-regulating process of CytoSorb, it is only able to remove 30-50% of cytokines at a time, which means that continued usage should not cause potential safety problems from the over removal of cytokines. OK, then what?
The differences in results between arms may be so minimal that a very large study may be necessary to show any statistical significance. A lack of statistical significance between arms of the dosing studies may be the reason for the news blackout. If indeed preliminary dosing studies are currently inconclusive, the original decision to embark on dosing studies as designed was inadvisable and would reflect badly on management.
How much money and time is CTSO willing to spend on studies that may remain inconclusive unless the dosing studies are extended perhaps for another year or even two years? Should CTSO stop its dosing studies and go as soon as possible to a US FDA approved study? Common sense would suggest that would be the best answer. That would imply shying away from KOL interest by shifting money to support a US trial. Do any of us outside the company really know how these KOL studies were designed in multiple centers?
One fact is very clear: investor enthusiasm is drying up. Whether the dosing studies are inconclusive or not, the point is investors need to be more fully informed so they speculate less. Management needs to stop hiding its head in the sand like a clueless ostrich.
Why is the short volume dead?
http://otcshortreport.com/index.php?index=ctso&action=view
Has the short volume dried up because the pps is low? Or has the short volume dried up, as I suspect, because LPC financing has diminished? Please note that at other times in the past when the pps was low, short volume was still high.
Is CTSO really going to the LPC well less often? We really have no way of knowing that I know of on a current basis, but if this is the case, why? One implication is that good news is anticipated and that CTSO anticipates being able to finance through a stock sale at a higher price within the next few months. This is speculation, of course, but it is curious that short sales have dried up.
We are becoming deranged.
The news blackout by DC suggests the worse. Without even partial news of interim results of dosing studies or updates on sales, distributors, or success stories, investors increasingly surmise results are not good. For example, on the Yahoo Message Board one typical commentator said, “Bad news is assured. It’s just a question of how bad.” Another commentator wrote, “Something is clearly wrong I believe. No trial results, missing all deadline goals, etc.”
The lack of periodic news is chipping away at investor confidence. Past representations that there would be news probably on dosing studies by late 2012 meant little. So making any more representations or updates seems pointless apparently to management. No explanation is even offered as to how CTSO will pay for expanded dosing studies.
Is the pps low because investor confidence is low? And why is investor confidence low? In large part I suggest the pps is low because there has been a news blackout following representations there would probably be an update on dosing studies by late 2012. Is it appropriate to question DC's credibility now? You bet it is.
Would you quit too?
If you were the CFO would you quit too? Sure you would consider it seriously if you had any sense. Now with prospects of continued effective financing based on a reasonable pps fading, CTSO plans to continue its dosing studies well into late 2013.
Where will CTSO get the funding to carry out these expanded studies? DC has certainly not told us and perhaps he did not tell the CFO Boccino either who had enough sense to see a derailment coming down the road and quit. Need you be reminded that before Boccino there was CFO David Lamadrid who also quit? Is it fair to conclude that DC is tough on CFOs with any degree of common sense?
CTSO remains foolishly optimistic that it can continue its profligate studies ad absurdum or at least ad nauseum. When these dosing studies are half completed you better bet DC will want more analysis leading to more paralysis, if not paraplegia. DC apparently believes that there are inexhaustible funds available for studies upon studies followed by more studies. The excuse now is the KOLs are really interested and CTSO must not pass up the chance to take advantage of their interest. On this critical issue of funding, could investors not be given just a modicum of analysis by DC and the CTSO Board?
Either CTSO gets a major partner to fund its profligacy or it terminates the dosing studies, accepts the results as they are, and applies for FDA approval of studies. Just the announcement of FDA approval of a study design for Cytosorb would do wonders for the pps.
But maybe it can’t do either. Maybe FDA approval of a trial format or a major partnership are unlikely without results of dosing studies or at least publication of the EU trial results in a reputable peer reviewed medical journal giving more substantiation to the results. So maybe CTSO is in a bind hoping against hope a financial White Knight will save it in time before its dosing studies end simply because there is insufficient cash on hand. Meanwhile CTSO investors must speculate in the dark in the absence of any meaningful IR from DC and CFOs will continue to resign.
SO WHAT!
What’s the big deal about the dosing study? The original purpose of the dosing studies as I understood them was to compare the efficacy of Cytosorb given for subset populations of sepsis patients with very high Interleukin levels and/or an age over 65 years of age with a “normal” population of sepsis patients not having abnormally high interleukin levels. Let’s suppose that the marginal differences now require a far bigger study group thereby extending the time of completion of the dosing studies to late 2013. So what! Is it really necessary to structure the FDA studies to incorporate findings from dosing studies? Because of the extension in projections of the FDA studies to late 2013 or early 2014 it would appear that this is still very much DC’s intent whether he is right or wrong in doing so.
My observation in life is that sometimes one needs to act on insufficient information. Analysis and more analysis can lead to paralysis – and I certainly worry about further delays leading to critical problems with financing for CTSO.
DC may be facing an inner intellectual struggle over these very issues. So allow me to suggest that if the interim results of dosing studies yet to be announced are equivocal leading to a sharp drop in pps, BUY, BUY, BUY! Trust DC unless he still fails to come up with a major partner over the next few months. If DC’s long range thinking is still that he wants the whole apple pie, SELL, SELL, SELL. Am I uncertain and a tad confused? You bet I am and so are investors -- and DC seems even confused himself to the extent that he might benefit from counseling.
SO WHAT!
Investors have lost faith in DC’s credibility. So what! After he predicted in 2010 the start of FDA studies in late 2011 or early 2012 he revised his projections in the SHL of 1/8/2013 to late 2013 or early 2014, some two years later. After repeatedly suggesting the dosing studies would be out by late 2012 we have yet to have a word about them. Following CE Mark approval in 2011, decent Cytosorb sales are still pending. OK, DC’s credibility is very much in question. Is this a big deal? My suggestion is not necessarily so. If you trust that the EU trial finding of a reduction in mortality using Cytosorb in sepsis patients is truly valid, you may be worrying too much even if there are serious questions about DC’s leadership.
SO WHAT!
OK, DC lacks good PR skills. OK, Cytosorb sales have so far been unexciting. OK, there is no partnership. OK, CTSO’s financial strength is in question. OK, DC projects in his talks and in his actions to be fairly rigid in his thinking, autocratic, arrogant, overly cautious, and unaccepting of any constructive criticism. OK, the pps has fallen 30% approximately the last month. But does any of this matter? Don’t we all know that DC is a brilliant internist and that doctors make good investors and CEOs? Who are we to question his leadership? He surely knows more than we do and of course he is far brighter than any of us. Nevertheless, there is considerable evidence so far that he may not be a very good long-range strategic planner. Get off the pedestal DC and announce a partnership.
HemoDefend and its modifications have huge potential.
From the last SHL:
“We have made significant advances in our in-line blood transfusion filter, demonstrating the ability to filter standard packed red blood cells (pRBCs) that account for nearly half of the 100+ million worldwide blood transfusions each year, while removing significant amounts of contaminants such as toxic free hemoglobin, and others. We have optimized the design so that a unit of packed red blood cells passes relatively easily through this low resistance, high flow filter by gravity alone in under a half an hour. This meets the requirements of the vast number of pRBC transfusions performed each year. We are also in the process of optimizing our packaging to help drive down the unit costs of each device. We also continue to make good progress on our "Beads in a Bag" configuration, with demonstration of our neutrally buoyant bead technology, and efficient removal of contaminants such antibodies, cytokines, free hemoglobin, and bioactive lipids over 42 days.”
For those who have been “hot and cold” like I have been on CTSO and its management and yet still psychologically able to buy on dips, this news really should be a boost for our confidence. Even if Cytosorb sales are a bust at least temporarily for one reason or another, and there have been excuses aplenty, a HemoDefend device able to do what was described above has the HUGE MARKET POTENTIAL if even just a small portion of the "100+ million worldwide blood transfusions each year" is entered. Now if Dr. Chan can only monetize this device quickly, all of us who have CTSO shares may end up feeling euphoric relatively soon. I would have thought a company announcement would have been appropriate from the reticent, ever so careful and methodical Dr. Chan.
Would it not be interesting if some day it would be considered medical malpractice not to use this device whenever blood transfusions are given particularly of "old" blood stored for two weeks or more?
Finally, good news was released 1/10/2013
with the confirmation of a new patent relating to HemoDefend like capabilities.
http://www.freepatentsonline.com/y2013/0011824.html
Title:
Polymeric Sorbent for Removal of Impurities From Whole Blood and Blood Products
Document Type and Number:
United States Patent Application 20130011824
Kind Code: A1
Abstract:
The invention concerns methods of treating blood, blood products or physiologic fluid to maximize shelf life and/or minimizing transfusion related complications such as non-hemolytic transfusion reactions such as fever, transfusion-related acute lung injury (TRALI), transfusion associated dyspnea (TAD), and allergic reactions by removing undesirable molecules in the blood, blood product or physiologic fluid milieu through use of a sorbent.
Inventors:
Chan, Phillip P. (Cherry Hill, NJ, US)
Capponi, Vincent J. (Monmouth Junction, NJ, US)
Golobish, Thomas D. (Princeton, NJ, US)
Ali, Humayra Begum (Princeton, NJ, US)
Application Number:
13/344166