Pluristem Therapeutics Inc (PSTI)

[Spideyboy]

Hi Scott and thanks for finding and posting this article.

From what I can gather from the data, I'm not too concerned about Entolimod. Though true one figure does confuse me a little.

From the Article, they analyse a multitude of trials in NHP and with administration of Entolimod at different time points.

From the first Table 1: "Efficacy of a single injection of entolimod in increasing 40-day survival of lethally irradiated NHPs when administered at different dose levels within 1–48 hours after TBI."

We see that they analyse the data using 2 different significance test. Fisher's Exact and Log rank. It appears that Log rank tests are best to look at as these are used for comparison of survival, and a Fisher's exact needs a "big enough" sample size, and here each study has a relatively small sample size.
https://en.wikipedia.org/wiki/Log-rank_test
https://en.wikipedia.org/wiki/Exact_test
Thus looking at the p-vale B results, we can see that we have a statistical benefit from Entolimod in:
- Rs-06: 40 microgram/kg dose (0.02) 70% survival
- Rs-09: 10 microgram/kg dose (0.003) 94% survival
- Rs-14: 10 microgram/kg dose (0.004) 100% survival

Therefore we would see that the 10 microgram/kg dose is the optimum does, and that the 40 dose has worse survival than PLX-R18

So the 10 microgram/kg dose as the competitor to R18. But then looking at the rest of the data something gets a little confusing.

(Something to also take into account is that based on the rodent PLX-R18 data, WBC, RBC & Platelet counts effectively return to normal levels, and while these show the normal level in mice, these levels and their respective counts would be the same for normal humans).

Now back to this Entolimod data, the thing I find that is a little confusing is that one would expect that after the Total Body Irradiation to 6.5-6.75Gy radiation, in the vehicle treated group the bone marrow stem cells that produce the WBC, RBC & Platelets would see a decline, and that these cells would not be replaced by the body on its own, hence why people die. But the article Figure 2, which shows the "Accelerated hematological recovery of peripheral blood in NHPs injected with Entolimod 16–48 hours post-irradiation." shows that in all groups, even the vehicle (non-treated) NHPs return to normal baseline levels. I would not have thought that this would be possible for lethally dosed NHPs to on their own return to normal within 28 days??
Especially given the understanding that Total Body Exposure to ration of +6Gy, causes up to 95% death without care and death occurring within 6 weeks (42 days).
https://en.wikipedia.org/wiki/Acute_radiation_syndrome
So why on earth does the data conistently seem to show that all vehicle treated animals are fine within 28days??

Also when looking at the data provided in Table 2 "Mean nadir values of neutrophils, platelets and hemoglobin in peripheral blood following total body irradiation and vehicle or entolimod treatment.", I'm not sure what the point of this table is.

With regards this table, first of all we should only care about data relating to the 10 microgram/kg dose as this is the only dose that seem to show better and significance relevant improvement over R18.
Thus in this table, that relates to only one data point, Rs-09, where the 10 microgram/kg dose was administered 1 day after TBI. First of all, 1 day after TBI is not realistic, and even in an emergncy setting we would expect at least 2 days from exposure to treatment, so not sure if this is even real-world relevant. Secondly while these Entolimod nadir values for WBC, RBC and Platelets do should a statistically significant increase, in real terms we are talking an increase of:
Neutrophils: Vehicle 0.01x10^3/microlitre, to 0.03x10^3/microlitre.
Platelets: Vehicle 8x10^3/microlitre, to 22.4x10^3/microlitre.

Now consider the normal range in a human for WBC is 4x10^3/microlitre, and Platelets is 150-400x10^3/microlitre.
So these Entolimod improved nadir levels would be physiologically useless and situation unchanged to a real human.

On the RBC level, the nadir is reported in g/L, and at 76.7. Again a normal human range would be 138g/L. So we are talking half of the normal range, again totally useless for a real human. I know these are Nadir data points but they are not exactly mind-blowing or clinical relevant so not sure the emphasis on these.

By comparison the murine data from R18 at 23days post exposure, brings the:
WBC count to 3.5x10^3/microlitre
Platelet count to 280x10^3/microlitre
and the RBC count to 5.5x10^6/microlitre (normal 4-5x10^6/microlitre).
So R18 bringing levels back to normal and clinically relevant range.

Therefore the problem here is how they have shown the data in Figure 2. Entolimod doing basically the same as Vehicle, but Vehicle should not have the blood count levels returning by themselves to normal levels within 28 days. Hence difficult to actually see what's going on here with Entolimod. And if the Nadir data points are anything to go off then I'm not impressed at all with Entolimod's potential.

It's all a bit fuzzy and almost looks like the data is analysed and geared to show as much of a positive view as possible.

Any thoughts on this. I may very well have missed something here.