Replies to post #59848 on NorthWest Biotherapeutics Inc (NWBO)

[Rkmatters]

You clearly don't understand my posts. You think I'm short, but I'm not.

The Company is in the process to reverse the "screen" halt decision. The decision is not "official" until the appeals process ends. We already know that the clinical trial is on "hold", so there is nothing new to report to shareholders if a hold has not been lifted. They can keep that appeals process going for a very long time - over a year in fact. But that doesn't mean the hold will ever lift. It does not mean the halt decision will be overturned. But, yes, the appeals process will end eventually. And eventually they will need to let us know something. I'm not expecting them to say much, other than "enrollment is closed".

One of the theories was that the hold was based on the first IA; and how it was not trending well for PFS. (A difference was not being seen between either arms during the IA peak).

This trial removes patient based on tumor growth and yet tumor growth may end up being a natural byproduct of an "immunotherapy" biological (if the therapy works); and if the "inflammatory" response shows up early when MRIs are taken often, it is going to affect the PFS endpoint.

First, this is how the trial records PFS event:

DEFINITION OF PROGRESSION AFTER ENROLLMENT
Progression, calculated from the nadir tumor burden (i.e. post operative, Baseline, or
Baseline 2), is defined as one of the following:
• In the case of complete resection during primary therapy: a new measurable tumor
at the site of the resected tumor, defined as a mass with a longest diameter equal to
or greater than 1 cm in at least one dimension. If progression is not defined by these
studies, treatment may proceed and determinations made at the next scheduled
MRI.
• In the case of incomplete resection during primary therapy: a 25% increase or
greater in the residual tumor if the recurrent portion of the tumor is at least 1 cm or
greater in its longest diameter, measured by MRI and confirmed by scans above as
attributable to tumor growth;
• If resection is indicated for recurrent disease, while radiographic criteria for
progression have not been met: surgical resection, subsequently confirmed as
progressive GBM by Pathology at the clinical site and to be confirmed by
independent pathology;
• Appearance of any new lesion/site at least 1 cm in at least one dimension or greater
measured by MRI and confirmed by scans above;
• Unequivocal progression of non-measurable disease (either non-enhancing disease seen only on T2/FLAIR images or enhancing disease not meeting size criteria for measurability), such that there is confidence that tumor growth has occurred;4
4 Radbruch et al. 2010: Neuro Oncol. 2011 Dec 6.
• Death: all deaths are counted as events for the primary endpoint.
Radiographic evidence of disease progression will be evaluated and corroborated by
independent radiology review to determine disease progression for purpose of this trial.
MRIs to assess disease progression are done every 2 months. Unscheduled MRIs or
other testing will be recorded in eCRFs. If, during unscheduled procedures, there is
evidence of disease progression, it must be confirmed through independent review as
described above.
TIME TO TUMOR PROGRESSION
Time to tumor progression is assessed from nadir tumor burden (post operative,
Baseline, or Baseline 2) to the date of the first observation of objective disease
progression measured by MRI and confirmed if necessary by scans as described above
in section 14.2.
Patients who have not progressed by the end of the study will continue to be followed
for tumor progression or tumor recurrence, for survival (Section 14.5) and for their
medical history.

The industry is trying to change the imaging standards, but this trial is already in progress.

And so, if the study is improperly designed and is removing patients due to outdated imaging standards that do not match the "immunotherapy" times -- standards which causes the removal of patients due to "inflammatory response", false progression -- then the REGULATORY reason to impose the clinical hold would fall under this:

(ii) The plan or protocol for the investigation is clearly deficient in design to meet its stated objectives.

The regulators won't want the study to continue to enroll new patients if the first IA statistical analysis is showing the PRIMARY endpoint of PFS might fail. A failure in the primary, makes it look like the vaccine is a dud.

BUT, a bad IA does not necessarily mean patients were NOT responding. It could mean that patients ARE responding. Some of those same "false positive" progression patients, who have now crossed over to vaccine are going on to live a long time (if falsely removed); and therefore the trial is likely being monitored for OS.

The other part of the bad IA theory is that NW Bio has been in discussions with regulators, to rally for a co-endpoint change since conducting the trial with a TUMOR ASSESSMENT endpoint may prove to be faulty - given this is an immunotherapy trial and PFS is a tumor assessment endpoint. It makes sense to also have OS. If they add a co-primary endpoint they may need to enroll many more patients, and that is why enrollment being opened again is important. However, that may meant it might not be possible...

IF the first IA is not trending well, BUT yet, patients are living a long time, there's a conundrum.
Problem is all the patients who crossover, are on open label vaccine and other drugs are being introduced, so it becomes difficult to say that is the vaccine causing the long-term survival. And so, again, the Company is likely attempting to advocate for a co-primary endpoint. And that means allowing OS to move from a secondary endpoint to a primary endpoint. Yet I suspect they are likely not having luck, because 9 months later, and no resolution has been reached.

BUT we do know that the study is being allowed to continue, until the end, at least for now; and unless there is a protocol change of some sort soon, the SECONDARY endpoint will need to be ROBUST, to fix a lagging PRIMARY endpoint in order to be successful.

And that is where I perceive the study to be at now, at this crossroad. It's to far along into the halt, so I suspect it will not lift. I suspect they will never report on a co-endpoint change. It won't mean they didn't try. AT the moment, patients data is accruing. But, depending on how many patients they enrolled, we may have to wait a long time for the study to reach its secondary endpoint OS to find out the trial results.

The company will need to raise a lot of money to get to the end of the study, and because we might not hear a peep from them for a while, the price can fall with the next raise (significantly) and the market cap will be depleted dramatically. Phase III trials of their nature are expensive to run, and so it isn't as simple as whether you think there's a chance for trial success, you also have to concern yourself with toxic financing. If near the end O/S is too high, that risk/reward won't be much. And that sums up what I meant. GL