Coronavirus epidemic: preparing for extracorporeal organ support in intensive care

https://www.thelancet.com/pdfs/journals/lanres/PIIS2213-2600(20)30060-6.pdf

Here is another article which was just published within The Lancet Respiratory Medicine, this article focuses on the resulting acute respiratory distress syndrome (ARDS), which requires mechanical ventilation and in the most severe cases, extracorporeal support.

"The level of severity of illness in patients infected by coronavirus depends on the presence of comorbidities and immune status of the person. "Immune dysregulation can lead to a progressive cascade of pathophysiological events leading to critical illness with multiple organ dysfunction".

"Because it is not possible to anticipate the extent of the epidemic and the consequent number of patients who require intensive care management, intensive care clinicians must be prepared to provide specific organ support treatments and to consider that this type of treatment might be necessary for a large number of patients." ...

"A call to action should be made to raise awareness of the different extracorporeal techniques, each with specific criteria and modalities of prescription, delivery, and monitoring."

Claudio Ronco and Jean Louis Vincent are both KOL's for Cytosorb therapy.

This article is in addition to the other one in the Lancet which was referenced in the press release last week:

http://cytosorbents.mediaroom.com/2020-01-28-CytoSorb-the-Wuhan-Coronavirus-and-Cytokine-Storm

Yes, TechMed is the distributor there

https://cytosorbents.com/cytosorbents-and-tekmed-collaborate-to-distribute-cytosorb-in-australia-and-new-zealand/

AEMD stock has quadrupled in recent weeks on pure coronavirus speculation by stock-promoting outfits. At September 30, 2019, the Company had a cash balance of approximately $800,000. The company raised $5M in recent weeks but with over $2M/Q cash burn the company has no improving fundamentals and will eventually crash back to earth.

China to exempt taxes for imports of products related to virus control:
https://www.reuters.com/article/us-china-health-taxes/china-to-exempt-taxes-for-imports-of-products-related-to-virus-control-idUSKBN1ZV3K0

Now we just need the National Medical Products Administration (NMPA) (formerly CFDA) and Centre for Medical Device Evaluation (CMDE)to grant one of these for the filter (you will need to use a browser with translation):

https://www.cmde.org.cn/CL0050/20392.html (application for special examination of innovative medical devices)

If selling direct to the mainland is not an option, then the Medical Device Control Office (MDCO) in Hong Kong should expedite the product registration so our distributor there can start selling them (as a special administrative region of China. Hong Kong has its own medical device regulations, separate from mainland China.

Bingo! Great post hemopure.

I was originally thinking that once they have positive REMOVE data, they would apply for Breakthrough Device Designation (replaced the previous Expedited Access Pathway or EAP designation) for the infective endocarditis indication, but as you stated, they seem to be signaling this might be the approval path they take.

I was actually surprised how quick they received this approval. On the last call back in November they said that with the transition that's occurring in Europe right now between MDD and MDR, that all the notified bodies were pretty much overwhelmed with the amount of work they have ad had no time time table on when it might be approved.

It would probably blow everyone's mind (including mine) if tomorrow they had a third press release announcing the Hemodefend IDE acceptance. One could only hope.

Patents were extended back in 2017 to include China, so there is the legal recourse.

"This composition of matter patent provides additional coverage of the Company’s base polymer system, and this and other U.S. and foreign patents in this family extend protection of CytoSorb and CytoSorbents’ core technologies into 2026 in the U.S. and into 2031 in China, Japan, Russia, and Australia."

https://cytosorbents.com/cytosorbents-strengthens-intellectual-property-portfolio-with-new-patents-issued-in-the-u-s-china-japan-russia-and-australia/

Cytosorbents inked a distribution agreement in April 2018 with Chong Lap (H.K.) Co. Ltd. to distribute CytoSorb in Hong Kong. Haven't heard much since then in terms of progress on product registration or other activity. Would be interesting to see if there ends up being some activity through this channel due to this crisis. It seems to be worsening by the day.

Agree with your assessment of a small company dealing with growth issues. Hemodefend activities for the past year have been plagued with problems from personnel issues at a key supplier, to tooling and filling issues. Below is a timeline of key updates this past year. One can only speculate that there are some issues related to this "bench testing".

Hemodefend updates:

3/8/19 This pivotal trial has been delayed due to the sale and loss of key technical personnel at our main parts supplier. However, we are working diligently with the new team at the supplier to reprioritize our project and we'll update investors on the timing of this trial soon.

5/7/19 We've brought the tooling back on track and have now started to get into the assembly of the devices. We're on schedule to submit the IDE for the second half here. That could lead to starting a clinic, but that all is going to depend on the IDE review by the FDA. But we've been able to pull things back in line, not quite where we were originally, but really we're pretty comfortable that we're going to be submitting the IDE in the second half here for sure. Okay.

8/11/19 We’re at the stage now where we’re actually beginning to fill devices specifically for what Phil alluded to earlier which was the bench-testing which is the next step that we need to complete in order to do the IDE submission.

Great write-up Hemopure. Might also add that a catalyst for direct sales in Switzerland will be the dedicated reimbursement code. From May of last year, Dr. Chan said that it was expected by the end of the year, so hopefully news on that front will be coming soon.

"Just to be clear, we have a procedural code now for CytoSorb, but it is not yet been assigned official reimbursement, right, so there is a dollar value that needs to be assigned to that procedural code and that has not happened yet, although we expect that to happen sometime in the next three to six months, typically year following the assignment of -- getting the code that it has reimbursement assigned to it. So, that is something that we believe will likely come online in this year.

I would add that even if by some miracle, they filed it sometime late December, it can take 30 days for the FDA to review the application and make a decision with management concurrence, which puts any type of announcement on the acceptance of the IDE in mid to late January.

Q3 CC transcript. I posted an excerpt from it below:

"Jason Kolbert
Hi, guys, thank you so much. I guess as we get to the end of an hour, it's appropriate to close on HemoDefend. I know you've mentioned that very, very briefly, but can you talk just a little bit about the plan to follow the IDE by year end and help me understand, you know, how a 2020 approval is possible. Thanks.

Phillip Chan
Sure, Jason, thank you. Let me hand it over to Vince, who's been leading this effort. Vince?

Vincent Capponi
Great. Thanks, Phil. Hi, Jason. So Jason, we're in the process right now of completing all the engineering, validation, et cetera, for HemoDefend IDE that also includes doing the external testing at several blood banks with respect to the device and removal of potassium. Our intent is to file by the end of the year. So we're actually in the process of preparing the IDE right now. So again, our goal is to file by the end of the year, and I think, you know, we're aggressively targeting that."

Also Dr. Chan opened the door that the IDE would not be filed by the end of the year from a comment he made during the IDEAS conference in Dallas on Nov 20: https://investorshub.advfn.com/boards/read_msg.aspx?message_id=152906473

Murph, yes REMOVE is a government sponsored and funded trial and the top line data looks like it is still on track for around mid-2020.

I had high hopes for Hemodefend approval next year, because it is a smaller trial and should take about 3-6 months to complete. Now that looks less likely as the IDE has not even been accepted and the trial probably won't start until Q1. Thus, even assuming the results are statistically significant when the trial does complete late 2020, you're still looking at 2021 for an FDA approval timeline.

The company really faltered in 2019 on the clinical and sales execution fronts and until investors can see some concrete improvements being made in those areas, the share price will likely continue to reflect that unfortunately.

Patients on life support

This was posted this past week in Journal of Artificial Organs:

Hemoadsorption treatment with CytoSorb® in patients with extracorporeal life support therapy: A case series
Karl Träger, Christian Skrabal, Guenther Fischer, ...
First Published December 23, 2019 Research Article
https://doi.org/10.1177/0391398819895287

Abstract
Introduction:
Extracorporeal life support is an increasingly used technique for respiratory and cardiocirculatory support. Besides primary organ dysfunction, an excessive systemic hyperinflammatory response can be the underlying cause for acute organ failure necessitating extracorporeal life support therapy, or it may be associated with the extracorporeal life support itself. Controlling this overwhelming inflammatory response using CytoSorb® hemoadsorption has been shown to be associated with improved hemodynamics and restored metabolic balance resulting in preserved organ functions.

Methods:
In this retrospective case series, we describe 23 patients undergoing extracorporeal life support therapy and CytoSorb hemoadsorption. Cytokine levels were monitored, hemodynamic and metabolic variables were recorded, and outcome measures such as duration of organ support, intensive care unit mortality, and hospital mortality were noted.

Results:
CytoSorb treatment was associated with a trend toward a reduction in plasma cytokine levels (first treatment median interleukin-6 pre 595 vs post 350?pg/mL (n.s.); second treatment median interleukin-6 317 vs 108?pg/mL, p?<?0.05), a reduced vasoplegic response resulting in a reduction in vasopressor requirements (first treatment median norepinephrine pre 0.15 vs post 0.02?µg/kg/min (n.s.); second treatment median norepinephrine 0.1 vs 0.02?µg/kg/min, p?<?0.05) as well as rebalancing of deranged metabolic parameters (first treatment median lactate pre-treatment 6 vs post-treatment median lactate 2?mmol/L, p?<?0.05). The hemoperfusion treatment was well tolerated and safe, without the occurrence of any CytoSorb device-related adverse events.

Conclusion:
Hemoadsorption may offer a potentially promising therapeutic option for critically ill patients undergoing extracorporeal life support therapy, with cytokine reduction and a consecutively mitigated inflammatory response, decreased vasoplegia, and improved organ function as seen in our patients.

Thanks Murph for highlighting this. This trial is probably the company's best shot at having something of substance on the clinical front in 2020, especially since the Hemodefend IDE has not even been filed yet and probably won't get started until end of Q1.

This was posted a while back from CG:

"It's probably unlikely that positive top-line data from REMOVE would be sufficient to pursue full FDA approval without CTSO needing to repeat the clinical trial in the US. However, given that infective endocarditis is a growing problem in the US, it's possible that once armed with positive REMOVE data, CTSO could apply for Breakthrough Device Designation (replaced the previous Expedited Access Pathway or EAP designation) for the infective endocarditis indication allowing CTSO to pursue additional supporting clinical data in the US after its approval for use."

Not in my opinion. All of his focus seems to be on nurturing the Fresenius relationship. He came over from Johnson and Johnson in 2013 but beyond the three major distributor partnerships (Biocon, Terumo and Fresenius), not much activity has occurred those agreements were signed years ago. Again, some of this has to do with the clinical progress. If they can ever get this Hemodefend IDE filed and the trial started, they may gather some interest from the two companies you mentioned.

This is a viable scenario and something I have always had an eye out for, but this falls squarely on Chris Cramer's shoulders as VP of Business Development - working on these opportunities. Further progress is needed on the clinical front unfortunately before partners will seriously consider that type of co-investment or a licensing agreement.

Acute Kidney Injury due to Rhabdomyolysis in a Child (India)

A case study posted this week on Indian Pediatrics:

A 6-year-old girl presented with rhabdomyolysis following a febrile illness. Polymerase chain reaction (PCR) for Influenza B and enterovirus was positive. Her serum creatine kinase (CK) and myoglobin levels were very high. She developed myoglobinuria with oliguria leading to acute kidney injury. Continuous renal replacement therapy along with Cytosorb filter resulted in good outcome.

https://www.indianpediatrics.net/nov2019/nov-974-976.htm

CytoSorb therapy may lead to improved 28 day survival.

Just posted on Twitter: Watch Prof. Can Ince introducing “Improved Outcome of Patients in Septic Shock.” ?? http://bit.ly/can-ince

Hemodefend IDE filing will most likely be announced in January

If you listen to Dr. Chan's presentation at the Three Part Advisors 2019 Southwest IDEAS Investor Conference back on Wednesday, November 20, 2019 in Dallas, TX, he said the IDE was going to be announced "in the next couple of months".

http://www.wsw.com/webcast/threepa30/ctso/

This opened the door that it more than likely will not get filed by EOY. I am hoping this isn't the case, but with any additional selling the last couple of weeks in December, I would prefer to see this announcement in January than it come out during these light trading weeks.

Don't forget that reimbursement also plays a big part

Having a clear path to securing reimbursement in the various countries and regions is very important to sales. Lack of reimbursement will limit market acceptance of an innovative technology even if it has clinical value.

Double column usage of Cytosorb in parallel

I posted this video from the Brussels conference back earlier this year in which Dr. Nierhaus presented a case where they used two filters in parallel within a 24 hour period, on a 36 year old woman who went into septic shock after a kidney biopsy.
https://investorshub.advfn.com/boards/read_msg.aspx?message_id=148056118

If you don't want to watch the entire video, he talks about the time frame and conditions in which they introduced the two columns (3:20 mark).

Dr. Axel Nierhaus of University Hamburg-Eppendorf - 'My very special Cytosorb case'

Cytosorb promising option for septic shock-Candida infection and type 1 diabetes

New article accepted for publication in Journal of Artificial Organs:

Cytokine adsorption as a promising option for septic shock and multiple organ failure due to Candida infection and decompensated type 1 diabetes mellitus
Gerd Klinkmann, Matthias B. Stope, Andreas Meyer
First published: 18 November 2019
https://doi.org/10.1111/aor.13606

Abstract
Type 1 diabetes mellitus (T1DM) represents one of the most common chronic diseases in childhood. It is associated with high morbidity and mortality rates due to a metabolic dysregulation, its immunosuppressive effects and a predisposition to fungal infections. Candidiasis is a severe infection and its prevalence has increased throughout the last decades.

We report the case of a 19-year-old female patient admitted to our Intensive Care unit with T1DM and Candida infection associated with severe metabolic acidosis.

In the absence of response to high dose catecholamine cardiovascular therapy and the presence of severe metabolic acidosis, a CytoSorb® cartridge was implemented into the extra-corporal dialysis circuit resulting in a stabilization of hemodynamics accompanied by a tremendous decrease in vasopressor requirements, a control of the hyperinflammatory response as well as a resolution of metabolic acidosis and regeneration of renal function. Treatment with CytoSorb® was safe and feasible without technical problems. Notably, this is the first case description reporting on the effects of CytoSorb® in a patient with Candida infection as part of T1DM.

https://onlinelibrary.wiley.com/doi/abs/10.1111/aor.13606

Rapid treatment of unexpected septic shock
Cytosorb continues to be used in some extraordinary cases involving pediatric patients. In this case it was an 11 month old child:

Rapid treatment of unexpected septic shock: a single pediatric case recovery for Septic Shock due to Streptococcal Arthritis using early extracorporeal cytokine adsorber treatment
Raimondo P; Ficarella M; Moliterni P; Sisto M; Cito F; Calabrese G; Milella L; Pediatric Department of Anesthesia and Intensive Care Unit (General and Post Cardiac Surgery) Paediatric Hospital Giovanni XXIII – Bari, Italy

"We present a case of a male patient, aged 11 months, hospitalized in our Pediatric Hospital Giovanni XXIII (Bari, Italy) and evaluated by orthopedist at admission for a huge right knee edema, caused by ß-HemolyticStreptococcus and Staphylococcus Aureus and developed in septic shock within 12 hours after the admission. The patient was transferred to Pediatric ICU, in pre-agonal conditions, not responding to septic shock conventional treatments.

After parental consent, we added the extracorporeal cytokine absorber treatment (Cytosorb) to therapy, as life saving treatment. After two sets of 18 hours, we obtained a massive reduction of inflammatory mediators (IL-6, IL-10 and TNFa), an improvement of PRISM III and SOFA Score, a decrease of cathecolaminic support and an improvement of respiratory and metabolic parameters. After 5 days, the patient was transferred to the pediatric ward."

http://www.purificationtherapies.com/wp-content/uploads/01/16-2/P37_Poster_CYTO_Milella_Case%20report%20pediatrico.pdf

Yeah, CC Abbott is at it again
Another biased and distorted article in which she selective includes and omits key information.

Not so disguised however:

"Thus, in my opinion, CTSO is an AVOID or SELL.
Thanks for reading.
Disclaimer: My article is not investment advice. I am not an investment adviser."

Interesting to see her timing to release such an article. Mako Research already beat her to the punch with the other bogus article which was put out there earlier this year, so most of the damage has already been done. However if you look back at when she released her last one in Aug 2017, the stock price took off after that for the next twelve months: https://yhoo.it/34RDjnq

Let's hope for a repeat of that. Maybe she is anticipating something like this for 2020, but that is probably giving her too much credit as she is only a scientist .....

Q3 takeaways

Below are some of the highlights that were notable for me from the Q3 conference call:

Sales team restructuring including the increased headcount took some time this year to get into place due lengthly recruitment process to find the right people in a very tight labor market in Germany, and in Europe in general, as well as challenging labor laws. Even though the number of direct sales countries has doubled from 5 to 10, the increase and restructuring was not fully in place in time to impact 2019. These investments in sales infrastructure should start paying off starting in Q4 so 2020 should see a significant increase in direct sales and margins.

New Head of International Sales that focused on distributors and partners and regional managers that reside in their respective region, instead of trying to manage those territories from Germany. This should bolster distributor sales in my opinion.

Doubled the customer facing salespeople in Germany and subdivided it enabling the sales reps to focus in on core accounts driving adoption in those key accounts. The sales run rate is about $2 million in sales per rep in Germany so it is a no brainer to expand the sales force in Germany because the opportunity is so great.

The average number of CytoSorb cartridges per invoice continues to grow at many accounts, demonstrating increased usage and adoption.

When Fresenius Medical Care negotiated the transition of their European countries to CTSO in exchange for exclusivity for Mexico and South Korea they were left with quite a bit of European inventory. They continue to make good progress selling against that inventory, but until, they get registration in Mexico and South Korea they are holding off on ordering, because they cannot transfer their European inventory to those countries. On the positive side the other two distributors they said had too much inventory earlier this year, are ordering now and they are back to kind of their typical order pattern.

Fresnius Mexico management team is very engaged and the registration sounds like it is pretty I think we're pretty close to getting done, possibly by the end of the year. It's currenlty with the Mexican Health Authority right now. FMC Mexico has already a lot of pre-launch activities being run by the FMC Mexico organization so it must be close. A side benefit of FMC Mexico is it rolls up under FMC North America so the company gets now some interaction with Fresenius sales team here in the states.

The company is aggressively pursuing expansion of label for ticagrelor removal. This is similar to what was done with bilirubin and myoglobin reduction label expansion in 2018. They are hoping to hear back from the regulator soon on their assessment of our filing. However, it may take longer than the label expansion did back in 2018 however because of the transition that's occurring in Europe right now between MDD and MDR and they stated that all the notified bodies right now are pretty much overwhelmed with the amount of work they have. Having Tiacgrelor as an approved label together with published study out of Hamburg which included the cost modeling and economic benefits shown, should provide a huge opportunity in Europe.

Regarding ticagrelor removal, an interesting comment was made during the analyst Q&A. It was stated that during the presentation of the company's data at the European Cardiothoracic Meetings in Lisbon last month, one surgeon who had actually used the device on -- two patients as an off label use not associated the company, indicated that he was basically just "shocked by the traumatic improvement he saw in terms of patients bleeding".

The Hemodefend IDE is still being worked on, which is dissappointing, but they reiterated they intend to have it filed by the end of the year. The usual "completing all the engineering, validation, etc." reasons were referenced for the delay but they also mentioned the external testing they are doing at the multiple blood banks is still not complete. It sounds like the de novo 510k route is what is being targeted having only 20 patients to recruit, so potentially if they get the IDE filed in the next month and get the trial underway starting early January, it might be possible to get Hemodefend approved in 2020.

I tend to agree with other posters speculation that Mortenson's departure is linked to the recent changes to their clinical team, and potentially as a result of the slow recruitment and progress being made on REFRESH and on other clinical fronts.

For long term investors in this company despite how disappointing 2019 appears to be, the company made some key adjustments, strategic decisions and investments which should pay off next year I believe. This is still a young company which is experiencing growing pains and mistakes but the key for me is how they recognize adjust to those.

Breakthrough devices "provide for more effective treatment or diagnosis of life-threatening or irreversibly debilitating diseases or conditions" according to the FDA's definition. The removal of ticagrelor during emergency cardiac surgery seems to be an unmet need and would enable these procedures to be performed safely in critically-ill patients, however this may not meet the FDA's criteria for a breakthrough device.

I am inclined to think that as the rates of infective endocarditis have doubled here in the US *, the company could apply for Breakthrough Device Designation for the infective endocarditis indication. This was pointed out on a post from the Yahoo board (see below)

* Rising heart infections tied to U.S. opioid epidemic
https://www.reuters.com/article/us-health-heart-endocarditis-opioids/rising-heart-infections-tied-to-us-opioid-epidemic-idUSKBN1WM1Y6

(CG post from Yahoo board)
"Despite what the FDA sometimes says about being willing to accept foreign clinical data, it's probably unlikely that positive top-line data from REMOVE would be sufficient to pursue full FDA approval without CTSO needing to repeat the clinical trial in the US. However, given that infective endocarditis is a growing problem in the US, it's possible that once armed with positive REMOVE data, CTSO could apply for Breakthrough Device Designation (replaced the previous Expedited Access Pathway or EAP designation) for the infective endocarditis indication allowing CTSO to pursue additional supporting clinical data in the US after its approval for use."

The announcement of the establishment of a new U.K. operating subsidiary, CytoSorbents UK Limited, to me was as significant as the new study. Shows that some business and financial strategic thinking went into this, as the new subsidiary enables them to be eligible for certain research tax credits that are expected to subsidize the trial by up to a third of the cost.

In previous years the company has had an anemic presence in the UK with a sub-par distributor (LINC Medical). Despite having an MIB review by NICE as an innovative therapy in 2016, there were very few sepsis studies that were conducted and the ones published did not do much in terms of moving the adoption needle. The company changed distributors in 2018 to Chalice Medical (https://www.chalicemedical.com/).

With this new study focused around removal of Ticagrelor during cardiac surgery, I think this could be a game changer in terms of building adoption in Europe. There are over 35,000 bypass surgeries a year just in the UK and from an analysis of individual surgeons' performance at the operating table which was done several years ago, it found that the United Kingdom's cardiac surgeons are among the best in the world, with more adults surviving surgery despite patients being sicker and older than elsewhere. The average mortality rate for all those bypass surgeries was around 1.8%.

The suppressed share price this year in my opinion is due to the slow pace of recruitment and the lack of significant progress on the clinical front, combined with the hit piece on Seeking Alpha earlier this year, the price has never recovered.

Operationally the company is still making strides towards operating cash flow breakeven which together with the recent government grants, at least minimizes the risk of further dilution while the trials progress.

With approval dates now out at the earliest 2021 (assuming Hemodefend starts early next year) and potentially 2022-2023 with REFRESH, barring any partnership announcement, the share price will likely remain in a low trading range. I think some of the institutions probably realize that approval is a ways a way and there are better places to park their money.

Video clip of Cytosorb during heart transplant

This was uploaded to You Tube this morning by a perfusionist during a heart transplant procedure.

There is no central tender board in Saudi Arabia except this central procurement board known as “Monafasat,” which is an E-Government Procurement project under the broader e-Government initiative in the Kingdom of Saudi Arabia. This tender board does not appear to be publicly exposed and I believe is restricted access to authorized companies that have been selected to bid.

In Saudi Arabia, every government agency has its own full contracting authority. In Cytosorbents case this is the Ministry of Health. Foreign companies that are interested in bidding on a government project have to do several things to be able to bid in this system. They must make themselves known to the specific government agency/ministry offering the project and when that project becomes available, the government agency/ministry selects bidders from a list of prequalified/known companies and invites them to bid for that project.

Here is a link to some information on Monafasat
https://www.saudi.gov.sa/wps/portal/snp/pages/e-Procurement

Saudi tender

Could this finally be that big tender that the company has been waiting on from Saudi Arabia? This was just posted:

https://translate.google.com/translate?hl=en&sl=ar&u=https://monafasat.etimad.sa/tenders/tender-details/tid/263125&prev=search

No details available as to the number of units but we have been told in prior conference calls that in some parts of the world like the Middle East, Turkey, etc. they work of large tenders that span multiple years.

Also, as a side note if you are scratching your head at the dates on this tender ('02/02/1441'), this is the Islamic lunar calendar (Hijri), these dates equate to Gregorian October 1, 2019.

Fresenius is focused on developing the critical care markets - this is their new growth strategy. They are the number one or number two player in installed base of dialysis machines around the world. After they acquired Next Stage, they are now neck-and-neck position with Baxter, Gambro, and be very well positioned to help gain market share in the U.S. market. Several years ago they also acquired another, a Germany company called Xenios and acquired a product called the Novalung, and Novalung is an extracorporeal membrane oxygenation-type technology, and it is very good at gas exchange, particularly carbon dioxide exchange. But these ECMO systems that are sold by most of the major cardiac surgery players are gaining rapidly in popularity as a way to help stabilize patients who have very severe respiratory failure (CytoSorb has been estimated to have been used in more than 2,500 ECMO treatments and can do something that the other ECMO systems can't which is reduce the inflammatory mediators that are driving continued lung injury and other organ dysfunction.)

Cytosorb fits with Fresenius' installed base of dialysis machines found throughout Europe and the rest of the world, in NxStage's machines that are a dominant player in the U.S. critical care market, as well as now the machines that they've acquired from Xenios, including the Novalung. It is prudent for Cytosorbents to continue to build on their relationship with Fresenius as the acute care strategy continues to develop, even though the sales impact for now appears to be muted. If an acquisition were to occur, Fresenius would look to take out Cytosorbents for much more than they paid for NxStage which was 5-6x sales as the company continues to move towards break even cash flow (I believe Fresenius paid $2B for NxStage and at the time they were still losing money).

The two most commonly observed toxicities with CAR-T-cell therapies are CRS, characterised by high fever, hypotension, hypoxia, and/or multiorgan tox­icity; and a CAR-T-cell-related encephalopathy syndrome (CRES), typically characterised by a toxic encephalopathic state with symptoms of confusion and delirium, and occasionally seizures and cerebral oedema. Rare cases of fulminant haemophagocytic lymphohistiocytosis (HLH), also known as macrophage-activation syndrome (MAS), which is characterised by severe immune activation, lymphohistiocytic tissue infiltration, and immune-mediated multiorgan failure, have also been reported.

The filter has been used on 10 cases of secondary HLH before
https://cytosorbents.com/cytosorb-treatment-of-hlh-the-parallel-to-cytokine-release-syndrome-in-cancer-immunotherapy/

The setup of this study has been in the works for a while as evidence by Dr. Chan's comments during the Q1 conference call.

"And in terms of CAR-T cell immunotherapy studies, it's very interesting, we have now been hearing about the first treatments of CAR-T cell immunotherapies in Germany. In fact, one of the first treatments was associated with cytokine release syndrome, but that was a relatively mild case and resolved with standard therapy. But I think that we are well-positioned to begin to generate data. In cytokine release syndrome, we are working with some of the major players in the field in Germany, and some outside of Germany, and hope to drive some additional data from first usage in CRS soon."

It will be interesting to see how quickly they can get patients enrolled in this study. It is positive to see that they are moving on this Bertha.

Congress of the Federation of Anesthesiologists and Resuscitators (link to programme)

https://www.congressfar.ru/assets/schedule.pdf

Congress of the Federation of Anesthesiologists and Resuscitators

Kutepov D.E., Khashukoeva I.Kh., Bazhina E.S. are presenting at this conference in October in Moscow on "The experience of using the CYTOSORB system in patients with septic shock:

Dr. Kutepove is with the Russian Federation President Administration Clinical Hospital #1, ICU Department, Moscow, Russia and has several published cases in the Cytosorb Literature Database including

Use of CytoSorb in a patient with severe polytrauma and rhabdomyolysis
http://cytosorb-therapy.com/wp-content/uploads/2018/01/CoW_032018_E_web.pdf

Use of CytoSorb in the treatment of subacute transverse myelitis complicated by sepsis
http://cytosorb-therapy.com/wp-content/uploads/2017/12/CoW_502017_E_web-1.pdf

Another regional tender order in Italy this past week for Aferetica. One year period - 80,000 EUR with the option to purchase an additional 48,000 EUR at a unit cost of 1,600 EUR per device ($140,000+ USD). I have seen several of these tenders over the past twelve to twenty four months, so it appears that Aferetica is continuing to see consistent growth.

https://arcs.sanita.fvg.it/media/uploads/2019/08/20/850.pdf

Midkine removal

The following is an excerpt from an article which was recently accepted for publishing in July by Frontiers in Immunology. It was a multi-center study in Germany and Switzerland.

Midkine is a a heparin-binding cytokine that can be helpful in the development, repair and diseases but also harmful when elevated for example as a result of trauma.

What is interesting to note that Midkine (MK) appears to enhance the angiogenic and proliferative activities of cancer cells. The expression of MK has been found to be elevated in multiple cancer types, such as neuroblastoma, glioblastoma, Wilms’ tumors, thyroid papillary carcinomas, colorectal, liver, ovary, bladder, breast, lung, esophageal, stomach, and prostate cancers. Normal levels in an individual is usually less than 0.5-0.6 ng/ml, whereas patients with these malignancies have much higher levels than this. In neuroblastoma, for example, the levels of MK are elevated about three times the level in Stage 4 of the cancer (one of the final stages) than they are in Stage 1.

This is the first article I have run across where studies were done with Cytosorb specifically as it relates to Midkine removal.


Midkine is elevated after multiple trauma and acts directly on human cardiomyocytes by altering their functionality and metabolism
Ina Lackner1, Birte Weber1, Meike Baur1, Melanie Haffner-Luntzer2, Tim Eiseler3, Giorgio Fois4, Florian Gebhard1, Borna Relja5, Ingo Marzi5, Roman Pfeifer6, Sascha Halvachizadeh6, Miriam Lipiski7, Nikola Cesarovic7, Hans-Christoph Pape6 and Miriam Kalbitz8*

1Clinic for Trauma, Hand, Plastic and Reconstructive Surgery, Ulm University Medical Center, Germany
2Institute of Orthopedic Research and Biomechanics, Trauma Research Center Ulm, Ulm University Medical Center, Germany
3Department of Internal Medicine I, Faculty of Medicine, University of Ulm, Germany
4Institute of General Physiology, Faculty of Medicine, University of Ulm, Germany
5Department of Trauma, Hand and Reconstructive Surgery, University Hospital Frankfurt, Germany
6Department of Traumatology, University Hospital Zurich, Switzerland
7Department of Surgical Research, University Hospital of Zurich, Switzerland
8Department of Trauma, Hand, Plastic and Reconstructive Surgery, Ulm University Medical Center, Germany

Background and Purpose: Post-traumatic cardiac dysfunction often occurs in multiply injured patients (ISS ?16). Next to direct cardiac injury, post-traumatic cardiac dysfunction is mostly induced by the release of inflammatory biomarkers. One of those is the heparin-binding factor Midkine, which is elevated in humans after fracture, burn injury and traumatic spinal cord injury. Midkine is associated with cardiac pathologies but the exact role of Midkine in the development of those diseases is ambiguous. The systemic profile of Midkine after multiple trauma, its effects on cardiomyocytes and the association with post-traumatic cardiac dysfunction remain unknown.

Experimental Approach: Midkine levels were investigated in blood plasma of multiply injured humans and pigs. Furthermore, human cardiomyocytes (iPS) were cultured in presence/absence of Midkine and analysed regarding viability, apoptosis, calcium handling, metabolic alterations and oxidative stress. Finally, the Midkine filtration capacity of the therapeutic blood absorption column CytoSorb?300 was tested with recombinant Midkine or plasma from multiply injured patients.

Key Results: Midkine levels were significantly increased in blood plasma of multiply injured humans and pigs. Midkine acts on human cardiomyocytes, altering their mitochondrial respiration and calcium handling in vitro. CytoSorb?300 filtration reduced Midkine concentration ex vivo and in vitro depending on the dosage.

Conclusion and Implications: Midkine is elevated in human and porcine plasma after multiple trauma, affecting the functionality and metabolism of human cardiomyocytes in vitro. If the application of CytoSorb?300 filtration for patients after multiple trauma is a promising therapeutic approach to prevent post-traumatic cardiac dysfunction requires further examination.

https://www.frontiersin.org/articles/10.3389/fimmu.2019.01920/abstract

EXAS received FDA approval for Cologuard in August 2014. What's interesting to note looking at a 5 year chart is that the price was around $16 at the time of approval and doubled over the next few weeks topping out at $32, but the real price appreciation occurred after their commercialization efforts began to take hold. At the end of 2014 the had less than $1M in revenue and no gross profit.

Compare this to Cytosorbents who has been steadily building upon their commercialization efforts outside the US with increasing revenues and 70+% gross profit margin. I am not sure how much preventative care costs are for hospitals and insurance companies (e.g. colonoscopies) but the company has said before that cost can be staggering in ICU stays due to the lack of active therapies. Patients can linger days to weeks at a time at a cost of $2,000 to $3,000 a day. Compared to a few Cytosorb filters at $1000 each. The US spends nearly 1% of its GDP on critical care medicine every single year.

Thanks Raptor for bringing this comparison to light. It gives long term shareholders some glimpse of the potential here.

New patent filed for endotoxin removal

Assuming this is for Cytosorb-XL as it combines lipopolysaccharide (LPS) endotoxin removal with the existing cytokine, toxin, and inflammatory mediator reduction.

https://patentimages.storage.googleapis.com/73/a6/a9/90f7a021d9e4a7/US20190201867A1.pdf

Blood Purification Journal Abstracts May 2019-47

This document was just published online (June) by an independent researcher, which contains over 20 published studies and patient cases where Cytosorb was successfully used in SIRS, Sepsis, MODS, Cardiac Surgery, ECMO, and Drug Removal. You have to scroll down one page but the entire document can be downloaded as a .pdf. Many of these studies have been published on the company's web site through the case of the week but there are some that I have not read.

Nephrologists, internists and hospital staff involved in dialysis, apheresis and immunoadsorption for acute and chronic solid organ failure read this publication. It's also a nice concise summary document you can forward to your physician friends and potential investors that may be interested in the technology.

https://bit.ly/2JizG20