Thank you for your comments and the questions raised. With the increase in SP, I'm noticing a few new names have joined the discussion recently and may also have similar questions than the ones you have raised. Whilst Google is a fantastic tool to DYOR, it is optional and may not always result in Hawksome70 results unless you know what to Google for, and in this instance, also know roughly what period to focus on.
I will try and keep it short, plus I know it is a bit unfair towards
@JB1975 as he also had a discussion going over on the MSB thread that I wanted to reply to. But given the usual claims that MSB owns everything under the sun and likely even the sun itself, I currently don't feel like digging through MSB's ASX releases (as my opinion was solely based on statements, not the science) that led me
believe that this time around the BLA should be successful.
Short version:
Whilst the data of an EAP itself does not constitute a clinical trial in that sense and given MSB's continuous statements that trial itself was an adequate study, it all came down to the potency assay as we all know and showing that it can be used to predict . The potency assay must have been in place at the time of the MSB-GVHD001 trial and as you have shown, required more data points that MSB could provide, hence resulting in CRL#1 and CRL#2.
This is where the EAP comes in with additional data points. MSB is under the opinion it seems that given they consider their 001 trial to "give significance to the results of the investigation as described in the Code of Federal Regulations for adequate and wellcontrolled studies (21 CFR 314.126)" (
https://www.aspecthuntley.com.au/asxdata/20230921/pdf/02714514.pdf), they did present additional data from the EAP to back up it up. This is based on the half yearly presentation bullet points 1-4 under GvHD and can be found here:
https://investorsmedia.mesoblast.com/static-files/b6ae5b0b-0873-4ee1-9967-f9a4d33729f4 and bullet point 1 n the most recent 4C here:
https://investorsmedia.mesoblast.com/static-files/59ef5b66-b6dd-4eb1-be54-78a65a9e4f5d. Caution however is to be taken and perhaps a Hawkseye70 needed, as the FDA has not made a decision yet, instead (and yet again - see CRL#2) is using the phrase "appears to be sufficient to support submission". That is not the same as a formal review, an opinion many formed in the lead up of CRL#2 when the FDA accepted the submission. I think in your last post referencing the patent application, you came across a reference of the additional data points, which I was going to cross-check against the ASX announcement references regarding the EAP in adults and the patent filing dates. But again, I haven't done that yet and am not sure if I can be bothered. That is not because I don't respect your research (which I do), but simply because of me allocating the little bit of free headspace left at present on different things.
Apologies, now coming back to the points you have raised
@Pledge.
Starting with your statement, "the primary focus of the company is the trials and the primary focus of the trials is GVHD."
That used to be false, but has now over the years become "less" false and almost right as a result of Cynata not being able to successfully deliver on the business model as initially intended. Sounds complicated, but really isn't when you look at the early years and comments made back then.
Originally (and that was one of the reasons I have invested back in the day), was to led other companies including MSB do the heavy lifting, show that MSCs work. Then, when the expected "multiple-donor-roadblock" comes up, being ready to swoop in with a clinically proven manufacturing process that can produce a consistent clinical outcome due to a homogeneous - although, I should really call it a less heterogeneous starting material given that all therapies will be manufactured from one single blood donation of one donor. Cynata did not intent to run the trials themselves, instead do one quick trial using an indication that provides data as quickly as possible to show that the manufacturing process works and subsequently the final product works at least the same or (likely) better than cells manufactured using the commercial process adopted by all other players in the industry at the time.
That is why GvHD was chosen as indication for the world-first clinical trial. An early streetwisereports interview explains this quite well:
TLSR:Cynata has engaged the Clinical Trial Company as the contract research organization for a Phase 1 study of the Cymerus technology. What is the design and time frame for that study?
SW:The Cymerus trial should prove that our manufactured mesenchymal stem cells are as good, or better, than any other brand. The trial is to treat GvHD with our patented MSCs. We are taking 16 patients into a Phase 1/2 study. We will dose them with our mesenchymal stem cells at a rate of 1 to 2 million cells per kilogram, or a few hundred million cells for each individual. We are looking at safety issues, but MSCs are already proven to be safe. At 28 days post-injection, if the patients are sitting up in bed or walking around, the product will have worked. I say that because death is the only alternative. It is a pretty dramatic trial design. The study will start during first half of 2016. We will have a readout quickly because the time frame for patients with immune rejection disease is short.
https://www.streetwisereports.com/pub/na/advanced-stem-cell-manufacture-saves-lives-and-prints-money-stewart-washer-of-cynata-therapeuticsBut apart from FujiFilm, who was the only iPSC player in this space at the time that had a vision which was shown in their acquisition of CDI, other big pharma players were still running their conventional processes to manufacture the final cell product and once you have spent the money to go through phase 1 and 2 trials, maybe even phase 3 trials, you are less flexible to start again as a result of switching your starting material.
I could go into detail about the framework change in Japan, which presented a unique opportunity for the likes of FujiFilm (FF) and Cynata in Japan, the shift of FF's plan to become one of the biggest if not the biggest CDMO in this space, rather than taking control of individual products and taking them through the clinical trial processes in Japan, the US etc. Obviously the COVID aftermath. It is already scattered throughout the threads over the years, but if needed (I doubt it), I am happy to go into these things a bit further again.
Cynata now realised that in order to get big pharma interested in partnering any of their indications, a single P1 trial just didn't cut it. Hence their initially proposed business model required a costly and lengthy adjustment - P2 trials are needed to show the world that the Cymerus process works. Rather than sitting back and waiting for pharma to come to them, they should have done a lot more in my opinion after the conclusion of the P1 trial to obtain more clinical data. Luckily, other researchers like Professor Hunter got interested in the possibility of testing a stem cell product that could potentially overcome issues he has experienced in his previous trial and couldn't be ruled out for the results to be a "mixed bag". Same as Professor Rabelink. Sadly, these partnerships are/were not the ones that came with licensing deals, but saved a considerable amount of funding that otherwise Cynata and subsequentlyus shareholders would have had to cough up to progress other indications such as P1/2a Renal and P3 OA trial. These trials would have not been feasible for Cynata to undertake if it wasn't for the majority of costs other than the product itself being externally funded. Unfortunately, no additional data was ready in the aftermath of MSB's CRL#1 or CRL#2 and the sales talent or lack thereof at CYP HQ became obvious. Many shareholders engaged with the company on numerous occasions, but a common indication of advice resistency was not something that even CYP-001 could overcome.
That leads me to OA and the mysterious 321/320 question. No need for Hawklock Homes70 to waste time more time than needed, as the reason for this was also fairly simple.
Here is the published protocol with comments:
https://bmjopen.bmj.com/content/11/11/e056382"The sample size allows for a drop-out rate of up to 20% over 24 months."
In November 2023, via ASX announcement:
"Following a review by the study statistician, which took into account the lower than expected dropout rate
observed thus far, the target sample size has been reduced to a minimum of 320 patients. The independent
DSMB confirmed that it considers this decision to be acceptable."
https://app.sharelinktechnologies.com/announcement/asx/5b9bea1527929d8f9c6c226b77092f1aYes, recruitment was slow, very slow. Especially at the beginning with lock-down restrictions in place. Luckily, Professor Hunter and his team managed to achieve a drop-out rate that was lower than expected and given the large sample size they have planned with to begin with, after reviewing by the study statistician, could also be reduced. The, when wrapping up the trial at 320, they enrolled one more patient, which is in line with the official study record:
https://www.anzctr.org.au/Trial/Registration/TrialReview.aspx?id=379726&isReview=trueThere is a lot more to say, more colour to be added, but will leave it at that for now.
I don't mind replying to a poster that - whilst I may not agree - is at least consistent with his views and criticism, no matter what stocks he owns. And that is something you do,
@Pledge. Discussion should however stay civilised. Humerous jabs however will always be well received.
Michelle out.
(20min delay)