I asked because I was wondering if the research method is at all relevant information for an investor. Apparently not? I find several sources according to which TP53m allelic status cannot be reliably obtained with the VAF method, but NGS is needed.
“… cases with seemingly monoallelic TP53^MT likely contain cryptic clones with biallelic TP53 inactivation, but their detection is not possible using traditional sequencing methods. Even after estimating the clonality of del17p or uniparental disomy (UPD), such TP53 configuration analysis is hampered by essential flaws such as the inability to: i) detect and quantify the biallelic fraction in cases with smaller variant allelic frequency (VAF) or ii) prove the presence of subclonal mosaicisms with two different TP53 mutant clones using traditional bulk DNA sequencing methods.”
Everything matters, but how relevant, I don’t know. This connection came to mind when I came across Syndax’s Beat-AML study on X. In it, MRD negativity was 100% by flow cytometry but only 31% by NGS.
Probably in biotech, it only applies before patent granting. The structure of the investigational drug must indeed be known to all parties. Regarding clinical results: I can’t see how precise reporting would benefit competitors - at least no more than Faron itself. Most biotechs I’ve familiarized myself with report clinical results in more detail than Faron.
Starting from 2min50sec in the video, some very interesting information about first-line responses is heard. According to what I heard, the first-line composite CR responses were 55% and CR responses were 30% according to IWG2023 criteria. A moment after that, it is stated that the CR response for TP53 mutants was 70%.
To me, there is a contradiction in these numbers; please tell me if I heard/understood what was said in the video incorrectly.
I understand. From some Faron material, I had already inferred that NGS would have been used. I interpret that old samples have been dug up for more detailed analysis and then TP53m was found.
I heard exactly the same. This has certainly not been made easy for investors, as the texts are full of composite CR and CR figures, IWG2006 and IWG2023 criteria, and TP53 subgroups, all mixed up.
Here’s how it goes for first-line treatment:
IWG2006:
CR 45%
WtTP53 CR: 20%
mTP53 CR: 70%
IWG2023: composite CR 55% (in Zeidan’s video above, according to the abstract this figure was for wtTP53 and mTP53 would have been 44%)
CR 30% (this was new information, at least)
The difference must come from the fact that IWG2006 is investigator assessed and IWG2023 is central assessment. So different people are evaluating the result. I believe the reason for the difference is the short-term CRs of transplant recipients that do not pass independent review. Let’s also remember that in the IWG2023 criteria, the Hb threshold has been lowered for CR, making it easier to achieve than with the 2006 criteria, so the percentages are precisely the opposite of what one might expect.
I assume here that the 30% CR mentioned by Zeidan also includes CRequivalent.
I don’t know if anyone can still follow this. Let’s just say in plain language that responses with bex+aza are at the same level as with aza alone when treating study patients.
Lest there be a misunderstanding, this interpretation is false concerning the TP53 mutation. Furthermore, your interpretation only applies to HR MDS wt patients. In addition, your interpretation focuses on CR.
I won’t bother, I’ll just quote smarter people. Here’s a recent publication by our esteemed Professor Zeidan. It costs a hundred. At the end, a tabulation of recent MDS trials and their responses.
We did not get the background for these nor the Kaplan-Meier. Likely a very heterogeneous dataset, and my concern about early censoring still persists.
So, as I said above, this is an investigator-assessed figure, meaning it’s biased, and central assessment does not reach the same figures, because for the entire first-line, it is 30% as Zeidan now told us.
Treatment response does not primarily determine whether a bone marrow transplant is performed. See HR MDS treatment guidelines. Deep response likely refers to MRD figures, the definition method of which is unknown, hence the NGS vs. flow cytometry difference here.
It seems to be on par with aza, if healthier patients are treated. See Bexmab inclusion and exclusion criteria.
Edit: it is still clearly higher than expected with aza, even considering patient selection. It’s worth digging up that Kontro poster and seeing how this result was obtained.
Edit2: In Kontro’s publication 11/2025 completely different figures, TD-TI in treatment-naïve patients 17%. I don’t have the energy to try and understand how the difference can be this large right now.
In all results, the small sample size and the resulting confidence intervals should be noted.
WOW. It was good that this figure was looked at more closely. The 57% figure is on-treatment TD-TI, not baseline TD-TI. Medically, these are completely different things.
Look at the wording of the poster, the swimlanes.
This explains the difference from the publication and the abstract.
Faron unequivocally provides misleading information in the press release. This is indeed a red flag!
The press release states: “For the first time, data shows 57% of frontline patients who were transfusion-dependent at baseline achieved transfusion independence, confirming restoration of healthy bone marrow function.”
In the ASH poster: “In treatment-naïve HR MDS, 57% of baseline TD patients became TI with BEX+AZA.”
I don’t really understand much of this, but do you really think this is incorrect information? Because I noticed that the poster I linked earlier has been removed from Faron’s website.
Faron should definitely come out and clarify these discrepancies and/or ambiguities in plain language. I find it hard to believe that they have tried to deceive the whole world. It’s easy to fool the forum crowd, but I imagine many external experts would have raised an alarm if the data had been distorted.
It’s still available from there, at least for me. But what exactly is incorrect now? The table clearly compares TD→TI data to the baseline in both places. Where exactly did you draw the conclusion that 4 do not belong to the baseline TD group? Why then compare 4/7? Or next to it, r/r TD baseline 23 and TD-TI 3/23? Or are you claiming that even here, that 3 does not belong to the original TD baseline 23?
If the denominator for both is x/7 (==baseline) and y/23 (==baseline), then it’s probably just a TD-TI conversion comparison made against the baseline. Otherwise, the denominators against which the comparison is made would not match the baseline.
From this, a total of 7 baseline TD→TI cases were then modeled on swimlane charts to visualize the TD→TI change.
So TD: transfusion-dependent
TI: transfusion-independent
These are medically 2 completely different things:
A) TD before treatment, which changes to TI
B) TI before treatment, during treatment TD develops which changes to TI
Point A is what is generally observed. Success in it indicates that the disease itself has improved.
Point B mainly indicates that as a combined effect of the disease and treatment, a temporary need for transfusions developed, which then resolved.
Faron communicates that A was achieved, 57% of patients who were baseline TD became TI.
In the poster, the left-hand table:
baseline TD 7. TD to TI conversion 4/7 (note! It is not stated that conversion is from baseline)
Swimlanes: the blue box starts when the patient enters the study. Treatment begins at the [ mark. You will notice that no one received a transfusion between study enrollment and the start of treatment. For most, the transfusion markers begin immediately after treatment. The caption states “patients who converted from TD to TI during bex+aza treatment”, no mention of baseline.
Thus, 4 patients are in category B, they were most likely baseline TI. Therefore, the result 4/7 = 57% cannot be reported.
I don’t know if this is pure incompetence or data spinning. Both happen.
As a layman, I’m not quite selling my shares because of this yet. Logically, TD has changed to TI. In both cases, BEX has been involved. AZA causes the need for (even multiple) blood transfusions, so at least to me, it sounds good that these can be avoided when BEX is included in the treatment mix.
It’s great that criticism and relentless challenging of data are present on the forum. Hopefully, Faron also understands that especially in this sensitive situation, there’s no room for error. If even the slightest ambiguity has arisen regarding the headline topic, Faron “must” throw a lifebuoy into the water on Monday - i.e., a clarification to the announcement.
Yes, in partnership negotiations, all raw data is on the table. As I understand it, Clark’s criticism does not concern the data itself, but how it was handled when the results were announced… In my opinion, transfers have been able to be reduced quite well in any case.
As an economist, I must also add that every avoided blood transfusion (about which there is no ambiguity here) saves a lot of treatment costs and hospital days (how much does 1 cost?). In addition, the patient’s quality of life without blood transfusion(s) is certainly better than in the transfusion circus…
I only read the introduction. Quote: “In this review, we discuss experiences from recently reported negative azacitidine studies where it was used in combination with eprenetapoptin (APR-246), magrolimab, pevonedistat, sabatolimab, tamibarotene, and venetoclax.” Was BEX included in those tables?
This has become a heavy thread to read, but I checked now that many new messages had come in, and the same rant continued here.
Well, I looked as requested, here are the swimlanes grabbed from the poster. 6/7 practically received a blood transfusion on the same day or within a couple of days of starting treatment, so the need for it could not have been caused by the treatment. The seventh one hasn’t needed many transfusions during treatment either.
My interpretation: these patients had transfusions before, not marked in the picture, or the need for a blood transfusion was present when treatments started, logistically it happened within a few days.
If something is still bothering you, a tip: it’s better to ask Kotro than to develop deep rabbit hole theories.
Thank you for your attention to a layman’s morning thoughts, while sipping coffee.
