The theme of this thread is "Analysis of the C-19 EAP" and I want to continue with that from a slightly different angle, still trying to size up the competitive landscape. We're often focused on trials and a BLA which have been discussed a lot on other threads. If competitors can't beat you to market with an approved product, there are other well-known tactics they might try to slow you down: disrupting supply chains, stealing customers... or influencing public opinion / decision makers / regulatory bodies, etc Each company tries to build a high wall and a moat.
We looked at the Khan and Newsome paper; there's another paper that was published in the Frontiers of Immunology just 4 days ago, May 19, that students of Mesoblast should know about. The title is the seemingly innocuous:
MSCTherapies for COVID-19: Importance of Patient Coagulopathy,Thromboprophylaxis, Cell Product Quality and Mode of Delivery forTreatment Safety and Efficacy
It's a detailed 9-page paper with an 88-reference bibliography, so there's a lot of important information to unpack. Note "Cell Product Quality" and "Mode of Delivery" in the title, I'll come back to those points. The authors, who have some prestige based on prior publications and position, are proposing CHANGES to the WHO and International Guidelines for administration of stem cells, so this is something serious MSB investors might want to take a look at. I'll start the discussion with an important DISCLOSURE: I am not interested in criticizing nations or nationalities or political persuasions. I am interested in getting to the truth about therapeutics: is a product safe and does it work and how should we as investors respond? Nothing more than that. ALL therapeutics should be held up to careful scrutiny imo, no exceptions. Since it was brought up on the thread I'll just say that we should distinguish the hard-working, good people of China from the CCP that rules over them. Likewise here, there is no political agenda on my part. I say it because the paper comes from the world-famous research and teaching hospital, Krankenhaus Charité, in Berlin, considered the number 1 hospital / medical school in all of Germany .... and there's a tie-in with Israel. I have great respect for the technology that comes out of both countries, but like I said, ALL therapeutics intended for human use should be held up to careful scrutiny.
The authors make some excellent points, but damage their credibility imo with this disclosure at the end: "The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."
Not trying to "construe" anything, let's start by taking the authors at their word and I'll let you be the judge. Before embarking on major modifications to WHO and International Guidelines, it's important to get a handle on conflicts of interest and motivations - and to make sure a COMPETITOR is not driving any proposed changes.. So, let's start with this press release from Pluristem, issued on - note the date - March 12: "Pluristem and Charité University of Medicine Berlin Join Forces Targeting Potential Treatment for Respiratory and Inflammatory Intra-tissue Complications Caused by COVID-19"
What a curious coincidence. Pluristem is working on a C-19 project with the same hospital as the authors of the paper - who are receiving European grant money but declare no conflict. Some will recall that on April 24 Pluristem announced its own grant so to speak, $50M in non-dilutive financing, a "loan", from the European Investment Bank. The purpose of the investment: "to Support Pluristem's COVID-19 Project and Phase III Studies". The terms of the deal among other things call for Pluristem to pay royalties to the bank starting in 2024... I wonder if anyone at the bank was surprised when on May 8 Pluristem announced the FDA had cleared it to begin a 140-patient phase 2 study, not the previously PR'ed phase 3... but maybe the reference was to ongoing phase 3 studies for other indications. No doubt.
Also on March 12, the CEO of Pluristem said this regarding the collaboration with Charité researchers: "The primary target is to PREVENT the deterioration of patients towards Acute Respiratory Distress Syndrome (ARDS) and sepsis. We intend to start the joint collaboration immediately..." (all-caps emphasis added by me). One week later he announced clearance to begin an EAP program in Israel; on April 7 he announced preliminary results from 7 patients in Israel; on April 13 that the EAP was expanding to the US; on April 24 the EIB loan; on May 8 FDA authorization to begin the phase 2; and on May 14 he announced 28-day results on 8 patients treated in the EAP (which I've discussed elsewhere).
On May 15 Pluristem registered its phase 2 RCT design online and it has some significant changes compared to the CEO's original statement. The goal is no longer to "prevent deterioration towards ARDS", it is now to "treat ARDS". Pluristem along with Athersys has come right in to Mesoblast's space for head-to-head competition in the C-19 ARDS market. One has to wonder if the clinicians treating patients at Charité perhaps advised against using PLX cells for "prevention". The trial is labeled "Treatment of Severe Covid-19", but the main inclusion criterion is "Meets definition of ARDS according to Berlin criteria". So, they've made a sophmoric mistake omitting ARDS and thus mislabeling the trial as "Severe C-19" rather than "Critical C-19" per FDA Trial Guidelines. With no specification in the design that intubation is a requirement, it leaves the goal of the trial a bit confusing in this day of HFNC... the other thing of note is the lack of P/F guidance, which they also failed to give in their EAP. It all suggests "mild ARDS" cases will be enrolled, so a lower bar than MSB has set. So far they are enrolling at two centers, one in NYC and one in Israel.
The other thing that stands out with this direct competitor is route of administration. The trial design calls for the administration of cells via Fifteen IM injections. In some patients there's repeat dosing in 1 week for a total of 30 IM injections. Pluristem has given IM injections in other trials including its phase 3 CLI and post-hip fracture studies. The rationale is that the cells have longer viability and perhaps increased opportunity for interaction with the patient's immune system. In this paper the German doctors also argue less chance of side effects in C-19 patients and ability to give a higher dose. I haven't surveyed physicians, but I suspect most would consider IM administration of a cell suspension a bit unusual. Certainly no other companies are choosing that route to my knowledge. Cells are ususally administered IV, think RBC's or WBC's for transfusion. Perhaps an argument could be made for outpatient IM administration for conditions such as CLI (chronic/critical limb ischemia). Prolonged duration of action is a rationale for giving other meds IM to outpatients. They linger longer and no need to start an IV or to take days of pills. In the ICU that advantage disappears. ICU patients all have central lines. Medications are routinely given IV that might have been given IM in the outpatient clinic. Long duration of action may not be an advantage in the ICU with an unstable patient and potential need to stop the medication quickly. If longer duration is needed a second or third or xth dose is easily given. ICU patients may have low blood pressure or shock and may not absorb medication deposited in a muscle remote from the lung problem. Rapid onset of action and ability to titrate dose or even stop the medicine completely become far more important than prolonged duration of action from bulk deposit. In addition, these patients may be prone to blood clots in the legs or development of large hematomas at the injection site. They are in twilight or unconscious and on ventilators. 30 injections?
IMO, having to do a full phase 2 represents a set back for Pluristem. Since they are already running phase 3 trials one would expect just a dosing lead-in with a small number of patients like we saw with Mesoblast and perhaps Athersys. Do they feel a need for a white paper to take to regulatory bodies... and for what reason?
Now on May 19 we have publication of this paper... and with all of the above as a brief introduction, I'll let you read through the paper and we can discuss it if anyone is interested. The authors do make many good points. They remind us that stem cells are a type of liquid organ transplant and should be regarded as such even though "immune privileged"... They remind us that stem cells from the local clinic down the street, that has little more than a centrifuge, may not be the safest. They remind us that many ICU patients have clotting abnormalities. Some are on anti-coagulants or anti-platelet agents. Some may develop full-blown DIC, with clotting and bleeding at the same time, with resulting high mortality (this tends to be a later complication and may be another reason for the 72-hour cutoff). They remind us in essence that these are very sick patients and no medication can be given carelessly. They express concern about TF/CD142 and point out it's actually expressed more with stem cells of placental (Pluristem) and adipose origin (we know of Takeda, does it explain why they haven't tried to re-purpose Alofisel... or have they in Spain?) They show us diagrams indicating "IV bad" and "IM good", without giving anything in the way of RCT evidence... and then they propose changes in international guidelines, despite nothing but favorable reports to date in using MSC's IV in C-19 ARDS. I suspect most of the precautions they mention are already in place with Mesoblast, the problem with clotting and diffuse endotheliitis would be well-known to MSB scientists.
Notice on page 6 where the authors make what Mark Twain would call a "stretcher" (ie of the truth): "Pluristem... (like Mesoblast and Athersys)... is also proceeding to phase II/III studies". Beeeeep. That might slip by most.
One thing that stands out for not being mentioned is the potential complication of giving IM injections to patients with clotting abnormalities. It's a general rule that IM injections are to be avoided in patients taking oral anticoagulants, not to mention patients on systemic anti-coagulants and problems related to C-19. Large painful hematomas may occur. In an unconscious obese patient who is anti-coagulated and receives 15 IM injections a surprising amount of blood loss might occur... that might not be visible externally and would not be painful in an unconscious patient.
The authors make three recommendations at the end of the paper to be taken to the WHO and the International Society for Cellular Therapy. Any thoughts? I'll let you read and be the judge of this paper and I'll discuss further with anyone interested. Too boring for the weekend??
MSB Price at posting:
$3.69 Sentiment: None Disclosure: Held
(20min delay)