Replies to post #139187 on NorthWest Biotherapeutics Inc (NWBO)

[doingmybest]

In my opinion, historical controls will be used more and more since there is just too much data and information to be utilized in adaptive trial designs. It is only logical that this information rich and time tested and reviewed huge data set is utilized, though, it is of course an area which will require much depth and understanding to apply. It is a perfect complement to AA, with confirmation to come post. It is not an easy endeavor and not without risks, or, it would have been used much more in the past. But, the time has come to build on well captured data and science to make for more efficient drug development.

[pgsd]

They have denied it in many ways and even recently. The recent update by Dr Bosch referenced modelling which itself modelled OS AND PFS. In doing so if it later turns out that they already was aware of an earlier indication of PFS failure or futility rec ( in contrary to other official statements I.e. 8k's etc previously provided) they would essentially be liable for hundreds and perhaps thousands of law suits for promoting the success these modelling attempts show. This is why it did not happen.

[flipper44]

The prior Rindopepimut nGBM trials (prior to Act IV) did not use carefully assembled historical controls. IMHO. Just more post Celldex CYA. Remember when they were pumping just before (Act IV) results? Remember when AF stopped pumping just before results and instead started warning because he supposedly talked to "shorts"? "Uh oh"

Control did not outperform an appropriate historical control MRD in Act IV. Celldex is wrong about that, imo.

Anyway, I'm certain you must have read the appendix graphs. http://www.thelancet.com/cms/attachment/2109603664/2082976630/mmc1.pdf

Even with MRD surgery of 2cm or less, the PFS (**finally released by Celldex) was only 8.0 PFS (post randomization) in the minimum residual disease treatment (MRD) group and 7.4 in MRD control group. Not what they obtained in prior unmasked/never blinded trials, and far from exceptional.

Dr. Liau wants to compare blended Rindopepimut with blinded DCVax-L trial. Wonder why?

Now she can, because Celldex released the blinded PFS results (in addition to previously released OS), which were not anything like the prior trial that were not unblinded. Wonder why Celldex waited almost two years to release PFS.

Look at these:

ACT III (n=65)
12.3 p = 0.0088 (approximatey 9.3 months from randomization) (Note: ACT IV (a masked/blinded trial) was 8.0 treatment and 7.4 Control)

Act II (n=22)
15.3 p = 0.0029 (approximately 12.3 months from randomization) (Note: ACT IV was 8.0 treatment and 7.4 Control)

ACTIVATE (n=18)
14.2 p = 0.0112 (approximately 11.2 months from randomization) (Note: ACT IV was 8.0 treatment and 7.4 Control)

Matched historical control (n=17)
"6.4" !!!!! You call these Matched ?!?!?! Had they used the right historical controls of 1 cm or less historical matched controls, it would not have been 6 months. You expect us to believe 6.4 was the historical match against 9.3 to 12.3???

BTW those earlier trials were 1 cm or less residual disease, where Celldex was 2 cm or less residual disease.

**In my opinion, Celldex reluctantly coughed up PFS results after Dr. Liau said they were important to compare and contrast with the current phase III trial. It was as I suspected, lower than all previous results and what would be expected in a group for minimum residual disease.

You kept going on about the NWBO DMC chairman.....you know what? He is very very vocal about other companies releasing their results so other companies can make suitable comparisons. Celldex held onto to their PFS results long after releasing OS. It is now clear to me why they were reluctant. IMO.

It makes sense to me why Dr. Liau was/is advocating to compare DCVax-L blinded phase III with Rintega blinded phase III.

[sentiment_stocks]

Hi Avii… your post to me didn’t show because your first line was comprised by code “

” and hence doesn't show up. So it could only be accessed on the moderator board. You probably hit the return button after that.

Regarding a supposed interim analysis to have been done in the Summer of 2015.

Two things.

One:
It's reputed that Les has denied this claim to several investors.

Senti, is he purported to have:
1. Denied an IA was performed in summer 2015? Or
2. Denied the trial failed in the summer of 2015? Or
3. Denied a futility rec in the summer of 2015?

I don't believe he is purported to have denied 1 or 3 above. I believe some have interpreted a denial of 2 above to mean a denial of 3. They are not the same thing.

Regarding your AA scenario : have you read the recently published Rindo paper in Lancet? Did you see what they said about historical controls? It was presented as an old lesson relearned.
"Even carefully assembled historical controls can be misleading and an unsuitable basis for clinical trial designs"

Regarding Les’ statement to a shareholder about whether a first interim analysis was done or if the trial failed in the summer of 2015… my recollection was solidly that it was in regards to whether an IA was done. Remember FKO/Koman was strongly suggesting that it had been done. And I believe it was Chris who then said it had not been done. I don’t recall it ever being a topic as to whether the trial had actually failed then. However, if it was, I’m sure you’ll find it, lol.

As for the historical controls statement you quoted above in the Lancet journal article on the Rindo trial.

http://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(17)30517-X/fulltext

First, I believe they are referencing using their own historical data - specifically the ACT III as a basis for the design of their P3 study. I think that because they reference this because the article states the following a bit earlier in the piece.

The results of ACT IV also question the predictive value of both historical control datasets (matched patients from non-study databases) and small randomised phase 2 trial datasets (such as ACT III) as a basis for the design of phase 3 studies.

I’d also like to suggest that any comparison to the Rindo trial would likely be considered “concurrent” and not “historical” as this trial was, for the most part, enrolled at the same time as the DCVax-L trial was. It enrolled from the same source population, however it did enroll a GBM subtype - EGFRviii. However, this expression is found typically in the classical subtype, although it is also found on the neural and pro neural subtype.

Specifically, the EGFR family of antigens including EGFR and ERBB2 were frequently found to be overexpressed at 80% and 24%, respectively, within the classical subtype, consistent with previous reports. Within the neural subtype, EGFR (54%) was frequently expressed; whereas within the proneural subtype survivin (32%) and Sart-1 (25%) were more commonly expressed.

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3881271/

So will this Rindo group fully represent the DCVax-L cross over arm group? Perhaps not, but I'd suggest that they represented the group who typically has a longer prognosis than those in the DCVax-L trial. As I understand it, they had fully resected surgeries, the classical subtype typically performs better with SOC, and it would seem they removed the rapid progressors from their trial and left the psPD patients in. In other words, acting as a concurrent control would mean they represent possibly the best performing GBM patients on SOC. But… regrettably, I’m sure you’ll find a way to argue that’s not the case. In the meantime, perhaps we can all look for the missing protocol for that Rindo trial.