Replies to post #62708 on NorthWest Biotherapeutics Inc (NWBO)

[Turtle65]

Well said Afford.......thx :) You put it perfect.

[Doktornolittle]

I have never complained about your frustrated posts. In fact I always pay attention to what you say about business issues. But there is venting, and there is just Bchng n Moaning. Somehow there is a difference.

[doingmybest]

I agree on the poor planning. I see it as they took a big gamble on their financing using non-traditional approaches and I think it almost worked. I think if not for the screening halt news that was unforeseen by them they would have retained sufficient financial strength because they then took a double whammy between their financing bashes and then a science bash, too much for a startup to deal with. That all being said, my thought is that it is important to know when to hold and when to fold. I still believe this is a hold and they will get themselves over the finish line here. I think I am being analytical about it when I say the science is too good to ignore. And, the backup is their IP and no one wants to think about their salvage value. But, I believe their immediate salvage value would do more than make us whole, and, the current hole NWBO is in is not an accurate reflection of their value but rather a market manipulated and perceived value. Worst case I believe I am fine, best case is a very good story with months and not years to wait.

[Pyrrhonian]

When NWBO goes silent, something's happening, that's for sure. And it's something about which they are wary over how the market will react, imo.

I wonder what happened last summer. They were finally on a decent pace enrolling in the trial, despite massive, unheard of funneling to Cognate--a NON-subsidiary of NWBO--of like $40mm cash over 12 months. I laid out these costs here, if anyone's interested (C = Cognate and NW = NWBO):

http://investorshub.advfn.com/boards/read_msg.aspx?message_id=118309698

Compare that with PCT, who charges about $15,000 to make a loaded dendritic cell vaccine--which I think is still frankly a bit expensive. Even still, they would have made 500 DCVax-L vaccines for about $7.5mm.

PHASE 3 CLINICAL TRIAL MANUFACTURING CONTRACT:

200 to 400 Units Produced:

$3,000,000 to $6,000,000

The deal Argos has with Invetech (until their own 100,000 sq.ft. facility--wholly owned by ARGS shareholders--is complete) is the same, $15k/vaccine.

When you think about how much has gone to Cognate over the years, you have to ask, "Why?" Not for vaccine costs, that's for sure. So what else? NWBO longs try to say it's for "massive expansion and preparations for commercialization, because it's important to hit the ground running." Well, what's massive? What has Cognate done wrt that for NWBO? The only sign of any expansion of any sort was this:

A Memphis biotech firm will add up to 80 jobs after a $9.47 million expansion of its offices and clean room.

Cognate BioServices Inc.’s permit filed with the city-county Department of Construction Code Enforcement shows 32,500 square feet will be added at 4600 E. Shelby Drive.

“What we are currently doing right now is expanding our manufacturing capacity,” Cognate chief operating officer Mike Stella said. “So we can grow with the companieS that we currently have as well as bring on additional clientS.”

Cognate employs about 60 people at 4600 E. Shelby. The company, based at Baltimore, opened the manufacturing plant in 2007 in Memphis.

“We specialize in helping companieS develop and then produce novel cellular therapies,” Stella said. “What (companieS) do is acquire intellectual property or technology out of universities and they want to further develop it, however once they get through the additional research and development they don’t necessarily have the manufacturing infrastructure to support it, and there we come in.”

http://www.commercialappeal.com/business/cognate-bioservices-to-undergo-947-million-expansion-ep-1193581019-323703911.html

When I looked for how big Cognate was at the time I found they were 35,000 sq.ft. not long before the time of that writing. So they made plans and began executing those plans to double in size and add 80 employees to their existing 60, and this massive expansion will cost just $9.47mm? And it's for their clientS--plural. Even if NWBO is their largest, it's not all for them.

Guys, where did $100mm in cash go? Where? And I'm not even mentioning the additional $70mm+ in warrants, shares and restricted shares. Just tell me at least where that $100mm in green backs went, please...

Even ARGS, building a 100,000 sq.ft. facility from NOTHING, has projected cost of about $25mm.

Where did $100mm, funneled over to Cognate, go?

The gross part in all this is that the trial could have been fully enrolled multiple times over with the money that has gone to Cognate, if they used PCT instead. Woodford himself sent over $90mm in CASH. In UNDER A YEAR, and they still couldn't get it done.

So, going back to my reason for even writing this, I wonder what happened last summer? We know they had:

-22 randomized by the restart (May 2011), and only had six or so more randomized by winter 2011-2012, but then ramped up a bit and got
-49 (total) randomized by mid Aug 2012,
-then had 80 or so end of 2012,
-then for 2013 finally got it going and had 170-180 randomized end of year, which caused
-the BSSR to trigger soon after at 192 randomized early 2014, then
-they changed protocol (probably lowered TLC requirement, added CD4+ analyses, changed enrollment total and event totals, etc), which caused some delay, then
-reported 300 randomized Aug 2015

you could say they were pretty ramped up right there. Also

-66 PFS events (over 40 "new") triggered Nov/Dec 2013, and at that rate and given the above enrollment ramp, 149 would trigger early spring 2015 and 199 before winter last year, then...

Hm. What does that mean? I still don't think any analysis of PFS endpoint would occur before full enrollment in this trial. Such as:

Planned interim efficacy analyses based on OS may be appropriate. However, interim efficacy analyses of PFS before completion of patient accrual are discouraged. Early interim efficacy analyses of PFS that cross a stopping boundary often overstate the magnitude of the effect. An interim PFS efficacy analysis is unlikely to provide an accurate or reproducible estimate of the treatment effect size because of inadequate follow-up, missing assessments, inconsistent readings between radiological reviewers, and/or lack of concordance between investigators and independent assessors. Stopping a trial based on interim PFS efficacy results that may not be verifiable after adjudication can render the trial results uninterpretable. In addition, a statistically significant difference in PFS that is small in magnitude may not be deemed clinically meaningful. --FDA Doc

That's some pretty serious stuff, and are general maxims in oncology, regardless of indication. Actually, the above is more relevant in GBM, because interpretation of scans can more often be confounded than in other solid tumor indications.

And we have precedent in this very trial. Linda and co got excited when the BICR (possibly just part of the CRO, or could be a separate hired entity) confirmed 66 events to trigger the analysis. Given their propensity to rush ahead with any possibly positive PR, they did so, only to shortly thereafter be informed by the DMC that nope--won't be doing any interim efficacy analysis.

Oops. The way they handled that whole thing thereafter (just went "quiet" on that for like a year or so, and never returned an official recommendation from DMC, obviously, and only said the "efficacy analysis remains outstanding" in SEC docs) compelled me to write a crazy piece on SA that suggested the DMC did an efficacy analysis (because that's what we were TOLD was happening in Dec 2013), returned a recommendation that got the ball rolling on a BLA submission while the trial continued on, accruing data for OS confirmatory endpoint. Actually a somewhat sound argument!

But that was then, and this is now. And THIS TIME we were not told a DMC did any analysis or any event point triggered it. Okay I guess you could say it happened anyway but this time NWBO just didn't tell us. Alright, if you want to assume that.

But, here's a more plausible guess, imo: The DMC told them "no go" on performing an IA for efficacy based on PFS primary because of that little quote above from FDA. Meaning, because the trial was not fully enrolled.

You could say it was NOT because they weren't fully enrolled but rather because the BSSR had not occurred yet. That's certainly possible, because the interim triggers would change. But is that the only reason? We can't say it just doesn't matter at all about full enrollment because mentions from FDA clearly state otherwise, and there are a number of examples of companies in communication with FDA that were warned by them not to perform an IA before full enrollment. AVII77 posted a bunch of these:

http://www.investorvillage.com/mbthread.asp?mb=6543&tid=13751152&showall=1

So if it's correct that 149 events occurred early spring 2015, then it's probably true that the DMC is not performing any analysis until full enrollment. Notice also for milestones for 2015, LP mentioned both completing accrual and performing interim efficacy analysis--meaning neither had happened yet. And perhaps giving away that the one (complete accrual) had to happen before the other (interim efficacy analysis).

If the above is true, then what happened summer 2015? They were on track to complete enrollment with Woody at the ready with another $30mm, and maybe ready with more to follow (despite vast over-charges from Cognate)--and then they stopped everything. STOP!

I wonder why. They were getting close. If they wanted to change anything in the trial, and if they knew they were close to full enrollment, and that once that happened an IA would occur and it would close the door on changes they may want to make (making major changes after unblinding is either impossible or greatly frowned upon)--then they would have to strike the iron while it was hot (last chance) and try to get some things changed.

It was probably all advised to them from someone. What changed out there? I can think of a couple things. One is the understanding of psPD and how difficult it is to control for them. Another are data like AV0113 that showed (according to them) the possibility that "ramping up the immune system" to get t-cells to target cancer cells can cause scans to appear as if the patient is progressing faster than they really are (the edema gets inflamed with immune cells). Thus messing up the PFS endpoint.

Another thing may be Optune possibly becoming SOC for ndGBM (even if it would take all the way through the DCVax-L BLA process and FDA decision to happen--could still mess up AA), making AA attempts that do not include Optune's use fruitless, as they would have to go for regular approval instead. But, problem with that is, PFS as primary is insufficient for RA in ndGBM.

Other indications, and especially unresectable metastatic indications, and especially 2nd and 3rd line, are fine to use PFS primary in. But fully resected, 1st line GBM is not one of them (as already stated by FDA to IMUC and also EMA to Genentech).

So how to solve these issues? Add 200-300 patients randomized 1:1 without crossover and make OS primary ep. Use PFS primary portion of trial as supportive, and perhaps for rGBM data, as placebo patients are usually given DCVax-L + Avastin upon PD; compare these PFS rates with NEW group of placebo patients given placebo upon PD. So, some interesting group comparisons come about, like:

-OLD placebo group (n=100) PFS post PD (as rGBM patients) vs NEW placebo group (n=100-150) PFS post PD
-OLD placebo group OS vs NEW placebo group OS
-NEW placebo group OS (non-crossover) vs NEW (n=100-150) and OLD DCVax group (n=200) OS

This is my guess as to what's going on. I think they want to increase sample size and redesign trial. I think if it doesn't happen they will terminate the study, and may or may not report results after 248 PFS events.

Please see this post for a different option:

http://investorshub.advfn.com/boards/read_msg.aspx?message_id=122671842

GLTA