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Thanks, oka. Definitely to east of highway. Situated on that side, it would be more suited to housing rather than commercial / science park kind of stuff, as on the other side. Existing nearby residents would object to anything high density.
If they wished, they could partner with a planning agent to draw up a scheme for planning application submission, but it would take minimum 18 months to get approval, and would probably involve re-submissions just like the Huawei scheme, imo.
But if you are a Kite or Juno taking a Car-T treatment to approval, then all the traffic lights on the route are switched to green and you get a special escort with outriders to ensure that your path is totally clear. And if you're a Covid vaccine you don't even have to go through proper trials. Warp speed ahead!
Hankman. Learning from experience, I tend to make what I consider realistic time estimates for myself, not best case estimates. Having said that, and seeing as you asked, I think best case is 6 months plus 6 months. 6 months to BLA submission and assuming they get priority review, 6 months for the FDA to do their deliberations. Realistically though, I personally wouldn't expect an approval decision until 18 months after topline.
They will get a waiver on the PDUFA fee though, so they won't have to pay for the FDA appraisal of their application.
For sure if they have stat sig on PFS and OS and no confoundment, that is the way they will go. But you really can't PR a firm intent to file a BLA, unless what you say about your endpoints is unequivocally in line with that.
I can't wish away the possible impact of pseudo-progression on PFS and crossover on OS. As far as we know, PFS is still the primary with most or all of the alpha spend. And we don't know the upshot of the adjudication process. That doesn't mean that I think these issues are insurmountable, but I do think they are issues.
That why I said months ago that an element of ambiguity in the topline wouldn't totally surprise me, even though it will present positively.
Uh no, topline WILL NOT be negative. Normally, a topline announcement is simply a brief statement whether the trial met its primary or secondary endpoints with statistical significance or not, then further data and analysis is presented in a peer-reviewed journal or conference a month or more later. That Northwest Bio intends to spend a few weeks with the full data and their SAB before even making any such announcement, indicates that they intend to be fully in control of the narrative. At a minimum, there will certainly be positive data (pre-selected MGMT Methylation Status) from the trial, which will be emphasized. Even if an endpoint did not reach statistical significance, the headline could still read something like” Northwest Biotherapeutics Announces Positive Survival Data From Phase III Trial of DCVax-L.”
Ev. I think you may be right on most of this. I had thought that NWBO were leasing the big warehouse building. So you reckon it's the little square white postage stamp thing? How disappointing!
It makes sense though because the big warehouse looks more like somewhere for dry commodity storage.
What you can clearly see from the Google Map is the green field site with the V shape notch at the top. That's almost certainly where Huawei are developing.. Do you agree?
..did show it on the east of the highway towards Sawston village. But I'd like to see something confirming that.
It's all fascinating intrigue to me. After first buying the site, why did NWBO spend $5m to buy an additional plot on the site, and what was that plot?
I know statues are rather out of fashion at the moment. But I think they should erect one in memory of Woody on the site. Coz he financed the original purchase!!
A huge amount of clinical work is under threat, and this analysis sought to identify biopharma’s most advanced, and most valuable, crop of R&D assets.
To pinpoint studies with the most invested – in terms of time and money – Vantage searched specifically for pivotal-stage projects that have yet to receive US approval, in trials that have a 2020 primary completion date, according to clinicaltrials.gov.
The topline analysis reveals 168 trials still recruiting, and another 147 that are active but fully enrolled, comprising 64,856 and 107,248 subjects respectively. Remarkably, it looks like at least five near-term blockbusters are under threat: Lilly’s tirzepatide, Reata’s bardoxolone, Immunomedics’ sacituzumab govitecan, Bristol-Myers Squibb’s Tyk2 inhibitor and Galapagos’s filgotinib.
The exposure of Bristol is especially striking: four Tyk2 studies are due to be completed this year, plus another four of ozanimod. The latter project features in the contingent value right issued under the Celgene acquisition; as Stat News has pointed out, FDA review delays could mean that this CVR never pays out.
Oops. Got my meters and feet mixed up. But the existing warehouse is still as big as what Huawei are developing on the map. And Huawei's main building isn't as big as it sounds because the FAB is separate and then there is the basement parking. Look at the illustration on your link. NWBO has the warehouse in grey.
And as far as I'm aware NWBO still have their own tenant:-
On October 10, 2017, we entered into an agreement to lease to Commodities Centre, a commodity storage and distribution firm domiciled in the U.K., an existing approximately 275,000 square foot warehouse building on the Company’s property in Sawston, U.K. The term of the lease will be five years, with the potential for the tenant to discontinue at three years and five months. The tenant will undertake at least $1.1 million of repairs and improvements to the building in return for five and a half months of free rent (which began upon execution of the lease and ends on March 24, 2018). Thereafter, the tenant will pay rent at an annualized rate of approximately $1.0 million for the first year, and thereafter rent at an annualized rate of approximately $1.4 million for each year or partial year for the rest of the lease term, plus VAT. The tenant will also pay a proportional share of the common costs and the insurance costs for the overall site. The tenant will pay for its own utilities and other costs for use of the warehouse.
Amazing. I don't know why, but I find it highly amusing that NWBO has a long term lease on the Vision Centre warehouse, which has more sq. footage than Huawei will have when they develop the rest of the site! Clearly Huawei wanted the site at pretty much any cost when they bought it, having to accept NWBO retaining ownership of 17 acres, and having to concede the long-term lease at a knockdown rent.
Now Huawei are going to spend a reported £1b on developing the site...
On December 14, 2018, we sold most of the U.K. property to an unrelated company. However, we retained a lease-back of the approximately 87,000 square foot manufacturing facility and adjacent areas for 20 years with a renewal option for another 20 years on favorable terms, and we retained ownership of a 17-acre parcel of property that we did not sell. Under the long-term lease of the 87,000 square foot facility, the annual rent is approximately $0.6 million, with rent reviews for potential increases (which are capped) only once every five years. Additionally, we will pay certain service charges of approximately $45,000 per year for the first 3 years, and approximately $55,000 per year for the next 7 years, and up to a potential maximum of approximately $110,000 per year for the remaining 10 years.
I'd like to know exactly where the 17 acres are in relation to the rest of the site.
But all of a sudden those acres are much more likely to be developable, because of the Huawei decision.
This might re-ignite the debate about NWBO and Huawei having a wider business relationship than purely landlord and tenant. I declare the debate re-open!
Gotta hand it to LP. Let's hope this display of acumen is not limited to real estate.
Beartrap. Thankyou for reminding me about the Expanded Access Arm.
I looked up the CT listing:-
Detailed Description:
Patients who are being screened under protocol 020221 who are not eligible for enrollment due to a) evidence of disease progression or pseudo-progression post chemo-radiation or b) insufficient (<5 doses) vaccine manufactured, and for whom the DCVax-L treatment was manufactured and released are eligible for this study.
Treatment Schedule:
Open label vaccine injections will be give per the associated 020221 protocol. Injections will be given at days 0, 10, 20, and at months 2, 4, 8, 12, 18, 24 and 30. There are no therapeutic restrictions, but guidelines for drug administration are recommended as per the 020221 protocol.
Data collected includes vaccine administration information, and any vaccine related adverse event. Patient MRIs will be collected centrally for future review. Patients will be followed for disease progression and survival.
So it was a way of providing access to L treatment for up to 99 patients who failed screening for the main trial. Not only for those who exhibited progression / pseudo-progression during the 3 months screening, but also for those for whom they were unable to produce enough L doses (probably because of insufficient tumor material).
The way I read it, this was really just a compassionate provision. Although it's called a study, there are no formal endpoints. Though patients are followed for progression and survival.
As you say, we really know nothing else about this EAP study, and the last entry on CT was in 2016.
For sure, it will provide some additional research indications. Such as how effective L can be on less than 5 doses. And they can review the scans themselves rather than it being done by central review, as I doubt that a CRO is even used to follow these patients. So they can see how a patient with a scan suggesting progression actually did subsequently. Potentially useful info and data, but I don't think it could possibly be used as standalone evidence to support approval for rGBM. But the fact that it is officially registered as a study suggests to me that it may have some possible use as supportive or supplementary evidential data for another study (perhaps one in the making), if that makes sense.
Then again, we don't know how many patients actually received L under this expanded access. They might have got up to 99 and stopped there basically to control cost. Or they may only have only recruited a handful. So I would applaud them for making this route available for patients who would have signed a consent form for the main trial, and undergone the leukapheresis only to fail screening, rather than just abandoning them. But I don't really consider it a controlled trial.
And I don't know why they had both the 55 patient info arm and then created this separate expanded access provision.
Just wondering if an email to Dr Bosch might answer a few (non-material) questions?
Company is not unblinded until TLD is completed and delivered.
You mean they are going to PR topline without knowing what's in it? No, perhaps you mean the Stats are going to deliver topline to the company.
'Topline data' is simply a term for whatever the company or trial sponsor decide to first release into the public domain. It would normally contain a few key significant outcomes and more often than not a reference to whether a primary endpoint has been met. And perhaps an indication as to when and where more comprehensive findings will be released, and whether a following regulatory application is intended. Obviously topline release has to be factually accurate, so as not to mislead, and it can't omit a clear adverse outcome, if one exists.
Whatever the Stat's data analysis finds and is communicated to the company, I wouldn't describe it as 'topline'. The company are going to want to know everything about every endpoint including the pre-defined subgroups. Not some abbreviated 'topline'.
From a data integrity point of view, I can see no real reason why the company has to remain blinded until after the Stats have had it for 'several weeks'. After final hard datalock, the results are immutable; they are what they are, and the final version of the SAP went in before the unblind. So why a requirement for the company to remain blinded for a further 'several weeks'? If there is a valid reason, I don't know what it is..
Though they might simply prefer to let the Stats do their stuff, without looking over their shoulder as they do it.
Just a small point, survivor: Landmark survival should really be milestone survival. They are used interchangeably somewhat, but there is a difference.
Milestone survival is defined as the Kaplan-Meier (27) survival probability at a time point defined a priori, such as two years. The word “milestone” is used in order to distinguish from that of “landmark.” The landmark method was first introduced by Anderson et al. (28) in an attempt to address the issue of bias in the analysis of survival when the covariate of interest is an on-study measurement such as tumor response status, ie, responders vs nonresponders. The landmark analysis excludes patients whose survival times did not exceed the fixed time point after initiation of therapy or random assignment. The survival curve using the landmark analysis will result in a plateau at 100% survival probability from time zero up to the chosen time point.
DISAGREE :If topline is negative , stock is zero within 60 seconds of that PR.Bankruptcy filed within 24 hours.55 lawsuits filed within 48 hours.No way insiders could get their debts repaid.His $250,000 covert is a binary, all or none, investment.Wallpaper for his retirement home if topline does not earn FDA commercial sales approval.
What makes you think topline announcement has to be a binary event?
Someone please comes up with an appropriate term for my action/behavior, like some kind of a syndrome, and I may print out and hung on the wall just behind my main computer.
Well, it was supposed to be a third. But at some point during the long trial, the ratio became a bit skewed, and ultimately it ended up being 29.9% instead of 33.3%. This only came to light when they published the JTM interim report on 29 May 2018.
And since then, this randomisation skew has been much discussed, as to how and why it came about. And there is no definitive answer.
It has been suggested that after the partial hold on recruitment was imposed in Aug 2015, when they had already randomised between 300 and 310 patients, that they were allowed to continue to randomise those already in the screening process, but only to treatment. Thus they managed to get to 331, with 232 being in treatment. The original target was 348. And two thirds of 348 is 232... So they fully recruited to the intended treatment arm number. But the control arm should have got to 116, and only got to 99. But the skew could have been there before the partial hold. We just don't know.
No end of reasons have been put forward as to why this might have came about. But nobody actually knows.
On the crossover issue. Patients can only cross over after having been deemed to have disease progression. Disease progression is the only trigger to cross over. (Though some of those progression decisions might have been pseudo-progression mistaken for actual disease progression.)
And patients got randomised after concurrent chemorad, which takes 3 months from surgery. If they progressed (or pseudo-progressed) during that 3 months, they were not randomised into the main trial, but were entered into the information arm, so they still got DCVax treatment.
And you are completely right that we don't have a 'clean' comparison between control and treatment on overall survival, seeing as two thirds of the control arm went on to receive DCVax after crossing over after progression. And the 30-33 who didn't crossover can't really be see as a representative control. Because individuals in this group were more likely to be 'iller'. Perhaps going straight to hospice after disease progression, and not wanting to cross to DCVax treatment. Or they were more likely to be the ones who 'jumped ship' from the DCVax trial, perhaps joining a different trial for patients with recurrent GBM, or just going missing completely ('Lost to follow-up'). And 30-33 is way too small a comparator anyway.
And that is why it was essential to carry on the trial to an unusual degree of maturity. To demonstrate that even if the arm by arm comparison has some confoundment (due to crossover), the survival of the treatment arm is wholly exceptional. Then you get into the vexxed question about whether comparison with 'historical controls' is valid and / or acceptable to a regulator. No straightforward answer to that one. Other than if survival is demonstrated to be 'out of the ballpark' good, then it becomes harder for a regulator to say no. The 'historical control' could be a similar treatment population in a similar trial (Optune is the obvious example), or simply the wider GBM population outside of a clinical trail. But that has its own issues because the ordinary GBM population is older on average and very much includes those who progress rapidly, or are immuno-suppressed. Basically, it will be a very helpful thing if DCVax-L treatment results comfortably surpass Optune treatment results, especially at all the milestones beyond 2yrs. So that means percentage survival at 2yrs, 3yrs, 4yrs, and 5yrs.
To say that the reducing of the control arm to 99 has 'little effect' is too sweeping an assertion. For maximum statistical power, you ideally have 1:1 treatment to control. 2:1 is bad enough; 70:30 weakens things further. You might end up with a p value of 0.04, when a slightly larger (or less lop-sided) ITT might have given you 0.05...
Alongside that you have the reduction from a planned 348 to 331 courtesy of the partial hold... More depowering.
Take these two power-reducing factors together (neither of which had been in NWBO's plan) and you effectively have a higher bar to negotiate.
Yes, she is clearly expecting the P3 to at least mirror the results from the earlier studies. And as of today, she will know the total still alive in the entire ITT (in blinded fashion). Not that she is about to say anything.
In terms of LTS, treatment meth will most likely be better than anything that has ever been seen before.
Marzan. It's actually about 16.50 where she makes the remark. She also prefaces the remark with; 'in all the trials that we have done'. So I don't think she is specifically referring to three dozen in this trial. Though there will very likely be at least 3 dozen 10yr survivors in this trial given a few more years.
Yes, there still could be a bit of rug-pulling. But I don't believe that will be down to the company. More likely some officious hospital administrator somewhere, preventing access (either in-person or remotely) to some key case records. That's why I think that if this is going to go on for a few weeks yet, they should keep us informed (with an implied; 'look, it's not us causing this' message, if necessary).
Yes. But I think soft lock can be different things in different cases. You could have all your data in; nothing missing at all. And you soft lock it. And then you do a final audit, before hard locking. Just a last QC check. I imagine that is a common process. To the extent that it is often not mentioned at all. Just a routine part of final scrubbing.
But, we clearly have a small amount of stuff still outstanding. I am not in any way suggesting it's the company dragging heels. I'm quite sure they want to get over the line as much as shareholders want them to.
The questions are (for me at least):- What is still outstanding? Is it all the data from the last few sites that still needs to be signed off? Or is it just the IDH status of a few dozen subjects from wherever. Can you (sensibly) move towards topline announcement, if some stuff is still missing? What is the anticipated duration of delay before everything is signed off and to hand?
And I'm sure the company is juggling with these issues right now. It must be really frustrating if you need an in-person visit to check a patient file, and that site is rigidly sticking to a Covid no access policy.
And (somewhat to myself), I ask whether there is some sort of deliberate delaying going on from a third party. If this was a Covid vaccine candidate in trial, nothing would be allowed to get in the way.
So I just think they need to keep us informed in these last few weeks by regular detailed updates, as the current situation requires. The last two times they gave us an update (including yesterday's 10-Q), the market was quite happy and hopped up a bit.
Final hard datalock is the milestone. And the culmination of a decade's work. The CRO will have completed its task. Then the company management can take a brief breather while the stats crunch the numbers for a couple of weeks.
I just don't want them to move to hard data lock, if there is important data still outstanding. It might come back to bite them if they do. (If it's only IDH mutation, then I don't think it's mission critical.)
Quite the contrary; he is pro-science. Just against the suppression of true science. Aren't you in favor of open access to and dissemination of genuine science? I don't throw in quasi references. If I throw in a reference, it's a reference, not a quasi reference. We can go through the recently cited references individually if you like.
The BP hegemony is a reality. It exists. It has huge impact at every level. It's the biggest threat to NWBO making progress, imo.
You don't have to agree with me, but if we are to debate, I would prefer that you stuck to the issues, rather than use judgemental and value-laden terms such as 'dress up', 'sneak stuff in', 'throwing in', 'throwing out'.
If you have a counter argument or position, why not put it forth?
Senti. Just have to point out the crossing curves and the excess mortality (well, actually, excess progression, seeing as this is labelled PFS) in the Nivo arm between about 3 months and 7 months. You know what that is, don't you...
But your point is well made. We won't have crossing survival curves, but we will have have curves that diverge more markedly beyond 24 months. (Hence the median is not the best metric..)
But when you get to about where we are now, diminishing returns start to set in, due to all cause mortality.
Nobody here has forgotten Direct, and everybody knows its unrealised potential. But there have been several false starts on Direct P2's in the last few years, due to them not having the necessary wherewithall. And that is definitely still the case. Everything has to be committed to concluding the L trial.
Unless a fairy godmother comes along.
(And if one does, imo that won't be Merck, as Merck will do nothing to advance the development of a drug that would potentially put at risk their revenue from a certain other top-selling drug. JMO.)
Not really... We don't know the gap between any softlock and the final data being available to proceed to hard lock. But every local investigator who signs off their site takes us closer.
Maybe the stats can get an earlier look than otherwise, but you can't go to topline if critical data is missing.
IDH data is not critical though, imo.
Just trying to be real, as I see no point in talking things up.
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